JP2021512046A - Macrocycles and their use - Google Patents

Abstract

The present invention is a novel compound having a tumor vascular remodeling effect and / or anti-CAF (cancer-related fibroblast) activity in an optionally pharmaceutically acceptable carrier (eg, formulas (I), (II)). , (III), (IV)) or pharmaceutically acceptable salts thereof, as well as their medical use.

Description

Related Applications This application is a US provisional patent application No. 62 / 586,416 filed on November 15, 2017; and a US provisional patent filed on August 20, 2018 under 35 USC 119 (e). Priority is claimed for patent application No. 62 / 765,310; the entire contents of each of these are incorporated herein by reference.

Technical Field The present invention provides a novel macrocycle having a tumor blood vessel remodeling effect and anti-CAF (cancer-related fibroblast) activity. The compound can be used, for example, to treat cancer in a subject or to inhibit tumor growth.

Background Halichondrin B and other halichondrin were originally isolated from the sponge Halichondria okadai (eg, D. Uemura et al. "Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge" J. Am. Chem. Soc., 107, 4796 (1985)), followed by anticancer agents found in Axinella sp., Phakellia carteri, and Lissondendryx sp. The total synthesis of halichondrin B was published in 1992 (see, eg, Y. Kishi et al. "Total Synthesis of Halichondrin B and Norhalichondrin B" J. Am. Chem. Soc., 114, 3162 (1992)). ). Halichondrin B exhibits in vitro inhibition of tubulin polymerization, microtubule assembly, beta5-tubulin cross-linking, GTP and vinblastine binding to tubulin, and tubulin-dependent GTP hydrolysis, providing antitumor activity in vitro and in vivo. (For example, Y. Hirata et al. "Halichondrins-antitumor hydrolyzed macrolides from a marine sponge" Pure Appl. Chem., 58, 701 (1986); Fodstad et al. "Comparative antitumor activities of halichondrins and vinblastine against human tumor" xenografts "J. of Experimental Therapeutics & Oncology 1996; 1: 119, 125).

Eribulin mesylate (Halaven ™) was developed on the basis of Halichondrin B (eg, WO 1999/065894 published December 23, 1999; December 15, 2005). WO 2005/118565; and W. Zheng et al. "Macrocyclic ketone analogues of halichondrin B" Bioorganic & Medicinal Chemistry Letters 14, 5551-5554 (2004)), currently eg, metastatic breast cancer. And clinically used in many countries to treat advanced liposarcoma.

Additional patent publications describing Harvardrin include Kishi et al., U.S. Pat. No. 5,436,238, which came into effect on July 25, 1995; Kishi et al., U.S. Pat. No. 5,338,865, which came into effect on August 16, 1994. There are WO 2016/003975 filed by Kishi et al., All of which have been transferred to the President and Fellow of Harvard University.

For example, US Pat. No. 5,786,492; US Pat. No. 8,598,373; US Pat. No. 9,206,194; US Pat. No. 9,469,651; WO / 2009 / 124237A1; WO / 1993 / 017690A1; WO / 2012 / 147900A1; US Pat. No. 7,982,060; US patent 8,618,313; US patent 9,303,050; US patent 8,093,410; US patent 8,350,067; US patent 8,975,422; US patent 8,987,479; US patent 8,203,010; US patent 8,445,701; US patent No. 8,884,031; US Patent RE45,324; US Patent 8,927,597; US Patent 9,382,262; US Patent 9,303,039; WO / 2009/046308A1; WO / 2006/076100A3; WO / 2006/076100A2; WO / 2015/085193A1; WO / 2016/176560A1; US Patent No. 9,278,979; US Patent No. 9,029,573; WO / 2011/094339A1; WO / 2016 / 179607A1; WO / 2009/064029A1; WO / 2013 / 142999A1; WO / 2015 / 066729A1; See also WO / 2016/038624A1; and WO / 2015/000070A1.

Cancer-associated fibroblasts (CAFs) are stromal cells that are widely found in a variety of solid tumors. CAF is well known to play an important role in angiogenesis, infiltration and metastasis. For example, invasive breast cancer (see, eg, M. Yamashita et al. "Role of stromal myofibroblasts in invasive breast cancer: stromal expression of alpha-smooth muscle actin correlates with worse clinical outcome" Breast Cancer 19, 170, 2012) and esophageal The amount of CAF and clinical prognosis in adenocarcinoma (see, eg, TJ Underwood et al. "Cancer-associated fibroblasts predict poor outcome and promote periostin-dependent invasion in esophageal adenocarcinoma" Journal of Pathol., 235, 466, 2015) There is a close correlation between them. CAF refers to various tumors, such as breast cancer (see, eg, P. Farmer et al. "A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer" Nature Medicine., 15 (1), 68, 2009). And head and neck cancer (eg, S. Schmitz et al. "Cetuximab promotes epithelial to mesenchymal transition and cancer associated fibroblasts in patients with head and neck cancer" Oncotarget, 6 (33), 34288, 2015; Y. Matsuoka et al. It is also reported that it correlates with resistance in "The tumor stromal features are associated with resistance to 5-FU-based chemoradiotherapy and a poor prognosis in patients with oral squamous cell cancer" (see APMIS 123 (3), 205, 2015). Was done.

Thus, it was observed that the tumor vascular remodeling effect and anti-CAF activity resulted in an improvement in the cancer microenvironment and assisted in the treatment of the tumor. Blood vessels are essential for tumor growth. Reconstructed blood vessels within the tumor can deliver anticancer drugs to the tumor in addition to reducing hypoxia. It has been reported that eribulin reduces the malignancy of tumors by remodeling the abnormal tumor vascular system to transform it into a more functional microenvironment and reducing hypoxia inside the tumor. Since the abnormal cancer microenvironment enhances drug resistance and metastasis, the apparent ability of eribulin to suppress these malignant transformations may contribute to its clinical benefit (eg, Y. Funahashi et al. "Eribulin mesylate". Reduce tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models "Cancer Sci. 105 (2014), 1334-1342). No anticancer agent having a tumor vascular remodeling effect and anti-CAF activity has been reported as of today.

Despite progress, additional compounds are needed to advance research and medical care in patients with tumors and cancer.

Outline of the present invention Halichondrin and its analogs and derivatives are useful therapeutic agents. Examples of halicondolin, its analogs and derivatives, and methods of using it, and methods of synthesizing it, are described, for example, in US Patent Application No. 2017/0137437, published May 18, 2017; International Publication WO 2016/003975 published on January 7; US Patent Application No. 2018/0230164 published on August 16, 2018; International Publication WO 2016/176560 published on November 3, 2016 US Publication No. 2018/0155361 published June 7, 2018; and US Pat. No. 9,938,288 issued April 10, 2018, each of which is incorporated herein by reference in its entirety. ) Can be found.

The present invention relates to macrocycle compounds (eg, compounds represented by formulas (I), (II), (III), and (IV)), and pharmaceutically acceptable salts thereof, and isotope labeling thereof. With respect to the derivatives made, and their pharmaceutical compositions. In some embodiments, the compound has a tumor vascular remodeling effect and anti-CAF activity.

The invention also provides, by way of example, a method of using the compounds provided herein for treating a proliferative disorder in a subject. In some embodiments, the invention is a method of using the compounds provided herein to treat a subject with cancer, a method for reversibly or irreversibly inhibiting mitosis in a cell. , And methods for inhibiting tumor growth in vitro, in vivo, or in a subject. In another aspect, the invention provides a kit comprising the compounds provided herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

式中：
Ｒ^Ｎ１およびＲ^Ｎ２は、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または窒素保護基であるか、任意にＲ^Ｎ１およびＲ^Ｎ２は、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルまたは任意に置換されていてもよいヘテロアリールを形成し；
Ｒ^Ｐ１は、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｘは、水素または−ＯＲ^Ｘａであり；
Ｒ^Ｙは、水素または−ＯＲ^Ｙａであり；
Ｒ^ＸａおよびＲ^Ｙａは、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であるか、任意に、Ｒ^ＸａおよびＲ^Ｙａは、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルを形成し；および
ｎは、１または２である、
で表される化合物およびその薬学的に許容し得る塩および同位体標識された誘導体を提供する。 In one aspect, the present invention relates to formula (I) :.

During the ceremony:
^RN1 and ^RN2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or nitrogen protecting group, or optionally ^RN1 and ^RN2 . Linked with intervening atoms to form optionally substituted heterocyclyls or optionally substituted heteroaryls;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, or optionally R ^Xa and R ^Ya. , Linked together with intervening atoms to form a heterocyclyl that may be optionally substituted; and n is 1 or 2.
Provided are a compound represented by the above and a pharmaceutically acceptable salt and isotope-labeled derivative thereof.

またはその薬学的に許容し得る塩または同位体標識された誘導体ではない。 In some embodiments, the compound of formula (I) is:

Or it is not a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

式中：
Ｒ^Ｎ１およびＲ^Ｎ２は、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または窒素保護基であるか、任意に、Ｒ^Ｎ１およびＲ^Ｎ２は、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルまたは任意に置換されていてもよいヘテロアリールを形成し；
Ｒ^Ｐ１およびＲ^Ｐ２は、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｘは、水素または−ＯＲ^Ｘａであり；
Ｒ^Ｙは、水素または−ＯＲ^Ｙａであり；
Ｒ^ＸａおよびＲ^Ｙａは、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であるか、任意に、Ｒ^ＸａおよびＲ^Ｙａは、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルを形成し；および
ｍは、０または１である、
で表される化合物およびその薬学的に許容し得る塩および同位体標識された誘導体を提供する。 In another aspect, the present invention relates to formula (II) :.

During the ceremony:
^RN1 and ^RN2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or nitrogen protecting group, or optionally ^RN1 and ^RN2. , Linked together with intervening atoms to form optionally substituted heterocyclyls or optionally substituted heteroaryls;
^RP1 and ^RP2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, or optionally R ^Xa and R ^Ya. , Linked together with intervening atoms to form a heterocyclyl that may be optionally substituted; and m is 0 or 1.
Provided are a compound represented by the above and a pharmaceutically acceptable salt and isotope-labeled derivative thereof.

式中：
Ｒ^Ｏは、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｐ１は、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｘは、水素または−ＯＲ^Ｘａであり；
Ｒ^Ｙは、水素または−ＯＲ^Ｙａであり；
Ｒ^ＸａおよびＲ^Ｙａは、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であるか、任意に、Ｒ^ＸａおよびＲ^Ｙａは、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルを形成し；および
ｎは、１または２である、
で表される化合物およびその薬学的に許容し得る塩および同位体標識された誘導体を提供する。 In another aspect, the present invention relates to formula (III):

During the ceremony:
^RO is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, or optionally R ^Xa and R ^Ya. , Linked together with intervening atoms to form a heterocyclyl that may be optionally substituted; and n is 1 or 2.
Provided are a compound represented by the above and a pharmaceutically acceptable salt and isotope-labeled derivative thereof.

またはその薬学的に許容し得る塩または同位体標識された誘導体ではない。 In some embodiments, the compound of formula (III) is:

Or it is not a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

式中：
Ｒ^Ｏは、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｐ１は、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｘは、水素または−ＯＲ^Ｘａであり；
Ｒ^Ｙは、水素または−ＯＲ^Ｙａであり；
Ｒ^ＸａおよびＲ^Ｙａは、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であるか、任意に、Ｒ^ＸａおよびＲ^Ｙａは、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルを形成する、
で表される化合物およびその薬学的に許容し得る塩および同位体標識された誘導体を提供する。 In another aspect, the present invention relates to formula (IV) :.

During the ceremony:
^RO is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, or optionally R ^Xa and R ^Ya. , Linked together with intervening atoms to form a heterocyclyl that may be optionally substituted,
Provided are a compound represented by the above and a pharmaceutically acceptable salt and isotope-labeled derivative thereof.

である化合物およびその薬学的に許容し得る塩；およびその同位体標識された誘導体を取り上げる。ある態様において、化合物（１）は、本発明から除外される。ある態様において、化合物（１）およびそのすべての薬学的に許容し得る塩およびその同位体標識された誘導体は、本発明から除外される。 In one aspect, the present invention relates to compound (1):

The compounds which are and their pharmaceutically acceptable salts; and their isotope-labeled derivatives are taken up. In some embodiments, compound (1) is excluded from the present invention. In some embodiments, compound (1) and all pharmaceutically acceptable salts thereof and isotope-labeled derivatives thereof are excluded from the present invention.

In another aspect, the invention provides a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof. The pharmaceutical composition may contain one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical composition may further comprise one or more additional therapeutic agents in combination, alternating or in other types of synchronized therapy to achieve the desired goal of treatment.

The present invention also features a method of synthesizing the compounds provided herein or their intermediates. Synthetic intermediates are also provided herein as part of the present invention.

The compounds provided herein have been found to have a beneficial effect on tumor vascular remodeling and have anti-CAF activity, as demonstrated in the drawings and examples. Therefore, the compounds provided herein have the potential to be used in the treatment of proliferative disorders. In some embodiments, the compounds include cancer (eg, squamous cell carcinoma of the head and neck (SCCHN), breast cancer, esophageal cancer, uterine cancer, ovarian cancer, rectal colon. It can be used to treat endometrial cancer, gastric cancer, lung cancer, small bowel cancer, bladder cancer, sweat adenocarcinoma, sarcoma, rare cancer).

In another aspect, the invention is to inhibit cancer treatment or tumor growth in a subject by means of the compounds provided herein or pharmaceutically acceptable salts thereof or isotope-labeled derivatives thereof. Providing a method. In some embodiments, the invention is provided by the compounds provided herein or pharmaceutically acceptable salts, or isotope-labeled derivatives thereof, for tumor vascular remodeling effects and / or in subjects, typically humans. Alternatively, a method of inhibiting any tumor growth or cancer in response to a compound having anti-CAF activity is provided.

The compounds or pharmaceutically acceptable salts provided herein, or isotope-labeled derivatives thereof, or compositions thereof, are administered in combination with any other active agent that provides beneficial results for the patient. You may. In one embodiment, the compounds provided herein are used in combination with immunotherapy, alternately or in other synchronized therapies. In some embodiments, immunotherapy is an anti-EGFR (epidermal growth factor receptor) antibody, anti-HER2 (human epidermal growth factor receptor), as described in more detail below. )) Anti-PD-1 antibody, or anti-PD-L1 antibody.

For example, a method of treating head and neck squamous cell carcinoma (SCCHN) in a subject in need of it, typically in humans, in which the subject is combined with anti-EGFR (epidermal growth factor receptor) mAb therapy. Methods are provided that include administering an effective amount of a compound or pharmaceutically acceptable salt provided herein, or an isotope-labeled derivative thereof, or a composition thereof. In certain embodiments, the anti-EGFR (epidermal growth factor receptor) mAb is cetuximab.

As another example, a method of treating breast cancer in a subject in need of it, typically in humans, in which the subject is combined with HER2 (Human Epidermal Growth Factor Receptor) mAb therapy in an effective amount of a book. Methods are provided that include administering the compound or pharmaceutically acceptable salt provided herein, or an isotope-labeled derivative thereof, or a composition thereof. In certain embodiments, the HER2 (human epidermal growth factor receptor) mAb is trastuzumab. In other embodiments, the compound is a traditional chemotherapy, such as adriamycin, cyclophosphamide, taxol, etc., or an anti-estrogen, such as a selective estrogen modulator (SERM). , Selective Estrogen Receptor Downregulator (SERD), Partial or Complete Estrogen Inhibitors (Fulvestrant, etc.), etc., or in combination with CDK4 / 6 Inhibitors, such as Palbociclib (Phizer), etc. It may be used to treat breast cancer.

Another aspect of the invention may be in the form of a hydrate, solvate, polymorph, stereoisomer or composition thereof in a kit which may be a dosage form package. Provided are a compound represented by (II), (III), or (IV) or a pharmaceutically acceptable salt, or an isotope-labeled derivative thereof. The kits described herein may include single or multiple doses of a compound or pharmaceutical composition thereof. The kit of the present invention may include instructions for using the provided therapeutic dosage form (eg, instructions for using the compounds or pharmaceutical compositions contained within the kit).

Therefore, the present invention includes at least the following features:
(I) A compound represented by the formula (I), (II), (III), or (IV), which may be in the form of a hydrate, a solvate, a stereoisomer or a polymorph, or a pharmacy thereof. Tolerable salt or isotope-labeled derivative;
(Ii) Provided herein to subjects such as humans for treating proliferative disorders in effective amounts, which may be in the form of hydrates, solvates, stereoisomers or polymorphs. A method for treatment comprising administering a compound, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof. In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is head and neck cancer (eg, head and neck squamous cell carcinoma (SCCHN), glandular sarcoma), breast cancer, esophageal cancer (eg, esophageal adenocarcinoma), uterine cancer (eg, esophageal adenocarcinoma). , Uterosarcoma), ovarian cancer, colonic rectal cancer, or sarcoma (eg, synovial sarcoma, angiosarcoma, soft tissue sarcoma, fibrosarcoma, uterine sarcoma, endosarcoma). In some embodiments, the cancer is bladder cancer (eg, urinary epithelial cancer), gastric cancer, small bowel cancer (eg, small intestinal adenocarcinoma), endometrial cancer, lung cancer (eg, non-small cells). Lung cancer) or sweat adenocarcinoma (eg, sweat adenocarcinoma). In some embodiments, the cancer is a rare cancer;
(Iii) Hydrate, solvate, or polymorph for use in treating subjects such as humans with effective amounts of medical disorders in response to vascular remodeling effects and / or anti-CAF activity. A method of treatment comprising administering a compound provided herein, which may be in the form of, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof;
(Iv) Formulas (I), (II), (III), which may be in the form of hydrates, solvates, stereoisomers or polymorphs for use in treating proliferative disorders. Alternatively, the compound represented by (IV), or a pharmaceutically acceptable salt or isotope-labeled derivative thereof. In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is head and neck squamous cell carcinoma (SCCHN), breast cancer, esophageal cancer, uterine cancer, ovarian cancer, rectal colon cancer, endometrial cancer, or sarcoma;
(V) Hydrate, solvate for use in treating medical disorders in response to vascular remodeling effects and / or anti-CAF activity (eg, proliferative disorders such as cancer or tumor). , A compound represented by the formula (I), (II), (III), or (IV), which may be in the form of a stereoisomer or a polymorph, or a pharmaceutically acceptable salt or isotope label thereof. Derivatives;
A deuterated derivative of the compound represented by the formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof;
(Vii) The compounds provided herein, which may be in the form of the hydrates, solvates, stereoisomers or polymorphs described above, or pharmaceutically acceptable salts or isotopes thereof. Treatment or prevention of proliferative disorders (eg, cancer or tumor) in response to vascular remodeling effects and / or anti-CAF activity, characterized in that one embodiment of a derivative, or active compound, is used in the manufacture. The process of manufacturing a drug intended for therapeutic use in order to
(Viii) Compounds represented by formulas (I), (II), (III), or (IV) in substantially pure form (eg, at least 90 or 95%), or pharmaceutically acceptable thereof. Obtaining salt or isotope-labeled derivative;
(IX) Compounds provided herein that may be in the form of hydrates, solvates, stereoisomers or polymorphs in pharmaceutically acceptable carriers or excipients, or pharmaceuticals thereof. A pharmaceutically acceptable composition of a pharmaceutically acceptable salt or isotope-labeled derivative;
(X) Provided herein which may be in hydrate, solvate, steric isomer or polymorphic form, optionally in a pharmaceutically acceptable carrier or excipient. Compound, or a pharmaceutically acceptable dosage form of a pharmaceutically acceptable salt or isotope-labeled derivative thereof;
(Xi) Formulas (I), (II), for treating disorders (eg, proliferative disorders) described herein that act by mechanisms other than the anti-CAF activity of the vascular remodeling effect and / or action. Compounds represented by (III) or (IV), or pharmaceutically acceptable salts or isotope-labeled derivatives thereof; and (xii) compounds described herein, and intermediates being synthesized. How to manufacture.

The accompanying drawings are incorporated herein and constitute a portion of the specification, exemplifying some embodiments of the invention, and together with this description, non-limiting examples of the invention. I will provide a.

FIG. 1 is a diagram showing the antitumor effect of compound (1) in a FaDu subcutaneous xenograft mouse model (head and neck cancer) as monotherapy described in Pharmacological Test Example 4.

FIG. 2 is a diagram showing the antitumor activity of compound (1) against an OSC-19 subcutaneous xenograft mouse model (head and neck cancer) as monotherapy described in Pharmacological Test Example 5.

FIG. 3 is a diagram showing the antitumor activity of compound (1) against a mouse model of HCC-1806 subcutaneous xenograft (breast cancer) as monotherapy described in Pharmacological Test Example 6.

FIG. 4 is a diagram showing the antitumor effect of compound (1) in a FaDu subcutaneous xenograft mouse model combined with cetuximab described in Pharmacological Test Example 7. CTX = cetuximab.

FIG. 5 is a diagram showing the antitumor activity of compound (1) in a KPL-4 subcutaneous xenograft mouse model (breast cancer) combined with trastuzumab described in Pharmacological Test Example 8.

6A-6B are diagrams showing the antitumor effect of compound (1) in the HSC-2 orthotopic transplanted mouse model. The tongue of nude mice, HSC-2 was introduced luciferase gene (1 × 10 ⁶ cells / spot) were transplanted. The amount of HSC-2 into which the luciferase gene was introduced was analyzed using an in vivo imaging system (IVIS). The data show the bioluminescence level in the tongue of each mouse. 6A-6B are diagrams showing the antitumor effect of compound (1) in the HSC-2 orthotopic transplanted mouse model. Typical bioluminescent image of 16 mice. CDDP, CTX and CDDP + CTX were used as controls. These are currently used in the treatment of patients with SCCHN cancer. CDDP = cisplatin, CTX = cetuximab.

7A-7B are diagrams showing the life-prolonging effect of compound (1) in combination with cetuximab in the HSC-2 orthotopic mouse model. The tongue of nude mice, HSC-2 was introduced luciferase gene (1 × 10 ⁶ cells / spot) were transplanted. The data show a survival curve up to 100 days after treatment with the drug (n = 16). CDDP = cisplatin, CTX = cetuximab. ^* P <0.0001 vs. compound (1) or CTX alone (Logrank (Mantel-Cox) test). 7A-7B are diagrams showing the life-prolonging effect of compound (1) in combination with cetuximab in the HSC-2 orthotopic mouse model. The amount of HSC-2 into which the luciferase gene was introduced was analyzed using an in vivo imaging system (IVIS). Bioluminescent images of 10 surviving mice in the compound (1) + CTX combination group on day 100. RBW = relative body weight.

8A-8B are diagrams showing the antitumor effect of compound (1) in combination with radiation therapy in a FaDu xenograft mouse model. The right femoral nude mice were implanted with FaDu into which luciferase gene is introduced (5 × 10 ⁶ cells / spot). Thirteen days after transplantation, mice were randomly assigned (n = 6), compound (1) was intravenously injected at 90 μg / kg on days 1 and 8, and 18 Gy of radiation was given on days 4 and 11. With or without therapy (RT) (Radio Therapy). The amount of FaDu cells into which the luciferase gene was introduced was analyzed using an in vivo imaging system (IVIS). The data show the average bioluminescence level and SEM up to day 1 (n = 6). SEM = standard error of the mean. ^* P <0.05 vs. 29 days without treatment (unpaired t-test). 8A-8B are diagrams showing the antitumor effect of compound (1) in combination with radiation therapy in a FaDu-transplanted mouse model. Representative bioluminescent images of each group of 6 mice on day 29. RT = radiation therapy.

FIG. 9 is a diagram showing the antitumor activity of compound (1) combined with the anti-mPD-1 antibody. A CT26 subcutaneously transplanted syngenic mouse model (colon cancer) was treated with compound (1) and anti-mPD-1 antibody on a Q7D schedule and a twice weekly schedule, respectively, for 2 weeks. The results show the average tumor volume ± SEM (mm ³ ) (n = 8).

FIG. 10A is a diagram showing a cell-free tubulin polymerization assay. Compound (1) has an inhibitory activity against tubulin polymerization. FIG. 10B is a diagram showing a microtubule dynamics assay. Compound (1) also has inhibitory activity on microtubule dynamics.

FIG. 11 shows that compound (1) is a potent antiproliferative agent in esophageal cancer (OE21, OE33, TE-8) and uterine sarcoma (MES-SA, MES-SA / Dx5-Rx1) cell lines. It is a figure which shows.

FIG. 12 shows that compound (1) has potent antitumor activity in subcutaneous xenograft models of breast and ovarian cancers (KPL-4 and COLO-704, respectively) as monotherapy.

FIG. 13 is a diagram showing the effect of compound (1) on the cancer microenvironment. As shown, compound (1) increases microvessel density. ^* P <0.05, ^** P <0.01, ^*** P <0.0001 vs. no treatment (Danet multiplex comparison test).

FIG. 14 is a diagram showing the effect of compound (1) on the cancer microenvironment. As shown, compound (1) reduces α-SMA positive CAF.

FIG. 15 shows that compound (1) reduces CAF-derived extracellular matrix (ECM) protein in the FaDu subcutaneous transplant model. A single dose of compound (1) 180 μg / kg + cetuximab was administered on day 1, and FaDu transplanted tumors were collected on day 6.

FIG. 16 shows that compound (1) exhibits a dose-dependent effect with cetuximab in a FaDu subcutaneous transplant model. Single dose, n = 6. Compound (1) and cetuximab (CTX) were administered on day 1 in the FaDu transplant model.

FIG. 17 is a diagram showing an antitumor effect in a mouse model of soft tissue sarcoma transplantation as monotherapy. MES-SA (human uterine sarcoma), HT-1080 (human fibrosarcoma), and CTG-2041 (human angiosarcoma) have been shown.

FIG. 18 is a diagram showing the antitumor effect of monotherapy in a mouse model of endometrial cancer transplantation. HEC-108 and AN3CA (endometrial cancer) have been shown.

19A-19H show that compound (1) reduced TGF-β-induced α-SMA expression in the in vitro CAF induction system. FIG. 19A. BJ cells (normal human lung fibroblasts) were co-cultured with FaDu cells for 3 days in the absence (vehicle) or presence of A83-01, a potent, selective TGF-β-R inhibitor, and α. -SMA expression was analyzed by immunofluorescent staining (red). Samples were also stained with antipan-human cytokeratin (green) for cancer cell staining and with DAPI (blue) for nuclear staining. 19B-19F. BJ cells were treated with compound (1) (0.15 nmol / L in immunofluorescent staining data and the concentration specified in Western blot analysis data) and TGF-β for 2 days. 19B-19E. Samples were stained with the specified antibody (red) and with DAPI (blue) for nuclear staining. FIG. 19F. Western blot images and image quantification. The graph shows the ratio of treatment group results to non-treatment group. 19G and 19F. BJ cells were pretreated with defactinib (1 μmol / L) and TGF-β for 2 days. The lens magnifications used were x4 (FIGS. 19A, 19B, 19C, 19G, and 19H) or x40 (FIGS. 19D and 19E).

20A and 20B. For α-SMA (FIG. 20A), phospho-S6-ribosome protein (Ser235 / 236) (FIG. 20B), of BJ cells treated with TGF-β (1 ng / mL) and compound (1) at the specified concentration. Quantification of immunofluorescence images. FIG. 20C. Immunofluorescence analysis of BJ cells treated with TGF-β in the absence or presence of the phosphatidylinositol 3 kinase inhibitor ductricib. FIG. 20D. Immunofluorescence analysis of phosphorylated Smad2 / 3 in BJ cells pretreated with compound (1) (72 hours) 30 minutes after stimulation with TGF-β. Acetylated-α-tubulin was co-stained to confirm the activity of compound (1). FIG. 20E. Western blot analysis of Smad2 / 3 in BJ cells treated with TGF-β and the specified concentration of compound (1). The lens magnification used was x4 (FIG. 20C) or x40 (FIG. 20D).

FIG. 21A. Immunofluorescent staining of α-SMA (red) and pan-cytokeratin (green) in TIG3 co-cultured with FaDu in the absence or presence of the FAK inhibitor A83-01. 21B and 21C. Immunofluorescent images of TIG3 cells treated with TGF-β and the specified concentration of compound (1) for α-SMA (FIG. 21B), phospho-S6-ribosome protein (Ser235 / 236) (FIG. 21C). Quantification. 21D and 21E. Immunofluorescence analysis of TIG3 cells treated with TGF-β in the absence or presence of compound (1) for β-tubulin (FIG. 21D), phospho-FAK (Tyr397) (FIG. 21E). FIG. 21F. Immunofluorescence analysis of TIG3 cells treated with TGF-β in the absence or presence of ductricive 100 nmol / L for α-SMA. 21G and 21H. Immunofluorescence analysis of TIG3 cells treated with TGF-β in the absence or presence of defactinib 3 μmol / L for α-SMA (FIG. 21G), phospho-S6-ribosome protein (Ser235 / 236) (FIG. 21H). The lens magnification was x4 (FIGS. 21A, 21F-21H) or x40 (FIGS. 21D and 21E).

FIG. 22. The antitumor effect of compound (1) in a mouse HS-SY-II (human synovial sarcoma) xenograft model as monotherapy.

FIG. 23. The antitumor effect of compound (1) in a HuTu80 (human duodenal cell) xenograft model in mice as monotherapy.

Definitions Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS Version, Handbook of Chemistry and Physics, 75th Ed., Inner Cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001 ; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , 3 rd Edition, Cambridge University Press, according to Cambridge, 1987 Will be done.

The compounds described herein can contain one or more asymmetric centers and thus can be present in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of individual enantiomers, diastereomers or geometric isomers, or are rich in a mixture of stereoisomers, including racemic mixtures and one or more stereoisomers. It can be in the form of a mixture. The isomers can be isolated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferred isomers are prepared by asymmetric synthesis. Can be done. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33: 2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) ); And see Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN 1972). The present invention also includes compounds as individual isomers that are substantially free of other isomers, or as mixtures of various isomers.

Unless otherwise stated, the structures depicted herein also mean that one or more isotopes contain different compounds only in the presence of enriched atoms. For example, replacement of hydrogen by deuterium or ^tritium, compounds having the present structures except for the substitution by ¹³ C or ¹⁴ C, or the replacement of ¹² C by ¹⁸ F of ¹⁹ F are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

When a wide range of values are listed, it is intended to include each value and a subrange within the range. For example, "C _1-6 alkyl" means C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C. _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 , and It is intended to include C _{5-6 alkyl.}

The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term "alkyl" refers to radicals of linear or branched saturated hydrocarbon groups with 1 to 10 carbon atoms ("C _1-10 alkyl"). In some embodiments, the alkyl group has 1-9 carbon atoms (“C _1-9 alkyl”). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C _{1 to 8} alkyl”). In some embodiments, the alkyl group has 1-7 carbon atoms (“C _1-7 alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C _{1 to 6} alkyl”). In some embodiments, the alkyl group has 1-5 carbon atoms (“C _1-5 alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C _1-4 alkyl”). In some embodiments, the alkyl group has 1-3 carbon atoms (“C _1-3 alkyl”). In some embodiments, the alkyl group has 1-2 carbon atoms (“C _1-2 alkyl”). In some embodiments, the alkyl group has one carbon atom ( "C ₁ alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C _{2 to 6} alkyl”). Examples of C _1-6 alkyl groups are methyl (C ₁ ), ethyl (C ₂ ), propyl (C ₃ ) (eg n-propyl, iso-propyl), butyl (C ₄ ) (eg n). -Butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C ₅ ) (eg n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl) , And hexyl (C ₆ ) (eg, n-hexyl). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ) and the like. Unless so specified, each presence of an alkyl group is independently substituted with an unsubstituted ("unsubstituted alkyl") or one or more substituents (eg, a halogen such as F) ("" Substituted alkyl "). In some embodiments, the alkyl group is unsubstituted C _1-10 alkyl ( _{such as unsubstituted C 1-6} alkyl, eg-CH ₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (such as unsubstituted C 1-6 alkyl, etc.). Pr, eg, unsubstituted n-propyl (n-Pr), unsubstituted iso-propyl (i-Pr)), unsubstituted butyl (Bu, eg, unsubstituted n-butyl (n-Bu)) ), Unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted iso-butyl (i-Bu)), in some embodiments, alkyl. The group is substituted C _1-10 alkyl (such as substituted C _1-6 alkyl, eg- _{CF 3} , Bn).

The term "haloalkyl" is a substituted alkyl group in which one or more hydrogen atoms are independently substituted with halogen, eg, fluoro, bromo, chloro, or iodine. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C _{1 to 8} haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C _{1 to 6} haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C _1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1-3 carbon atoms (“C _1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1-2 carbon atoms (“C _1-2 haloalkyl”). Examples of haloalkyl groups are -CHF ₂ , -CH ₂ F, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CF ₂ CF ₂ CF ₃ , -CCl ₃ , -CFCl ₂ , -CF ₂ Contains Cl and the like.

The term "heteroalkyl" refers to at least one heteroatom (eg, 1) selected from oxygen, nitrogen, or sulfur within the parent chain (ie, inserted between adjacent carbon atoms in the parent chain). Refers to an alkyl group further comprising (2, 3, or 4 heteroatoms) and / or located at one or more terminal positions (s) of the parent chain. In some embodiments, a heteroalkyl group refers to a saturated group having 1-10 carbon atoms and 1 or more heteroatoms in the parent chain (“hetero C _1-10 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-9 carbon atoms and 1 or more heteroatoms in the parent chain (“hetero C _1-9 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms in the parent chain (“hetero C _{1 to 8} alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-7 carbon atoms and 1 or more heteroatoms in the parent chain (“hetero C _1-7 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms in the parent chain (“hetero C _{1 to 6} alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain (“hetero C _{1 to 5} alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain (“hetero C _1-4 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-3 carbon atoms and 1 heteroatom in the parent chain (“hetero C _1-3 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom in the parent chain (“hetero C _1-2 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom in the parent chain (“hetero C ₁ alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain (“hetero C _{2 to 6} alkyl”). Unless so specified, each presence of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”). In some embodiments, the heteroalkyl group is an unsubstituted hetero C _1-10 alkyl. In some embodiments, the heteroalkyl group is a substituted hetero C _1-10 alkyl.

）は、（Ｅ）−または（Ｚ）−二重結合であってもよい。 The term "alkenyl" is a straight or branched hydrocarbon having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (eg, 1, 2, 3, or 4 double bonds). Refers to radicals of hydrogen groups. In some embodiments, the alkenyl group has 2-9 carbon atoms (“C _2-9 alkenyl”). In some embodiments, the alkenyl group has 2-8 carbon atoms (“C _2-8 alkenyl”). In some embodiments, the alkenyl group has 2-7 carbon atoms (“C _2-7 alkenyl”). In some embodiments, the alkenyl group has 2-6 carbon atoms (“C _2-6 alkenyl”). In some embodiments, the alkenyl group has 2-5 carbon atoms (“C _2-5 alkenyl”). In some embodiments, the alkenyl group has 2-4 carbon atoms (“C _2-4 alkenyl”). In some embodiments, the alkenyl group has 2-3 carbon atoms (“C _2-3 alkenyl”). In some embodiments, the alkenyl group has two carbon atoms (“C ₂ alkenyl”). One or more carbon-carbon double bonds can be present internally (such as 2-butenyl) or terminally (such as 1-butenyl). Examples of C _2-4 alkenyl groups are ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C 4). C ₄ ) etc. are included. Examples of C _2-6 alkenyl groups include the aforementioned C _2-4 alkenyl groups as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ) and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ) and the like. Unless so specified, each presence of an alkenyl group is independently unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C _2-10 alkenyl. In some embodiments, the alkenyl group is a substituted C _2-10 alkenyl. In the alkenyl group, the stereochemistry of the C = C double bond has not been specified (eg, -CH = CHCH ₃ or

) May be a (E) -or (Z) -double bond.

The term "heteroalkenyl" refers to at least one heteroatom (eg, 1, 1,) selected from oxygen, nitrogen, or sulfur within the parent chain (ie, inserted between adjacent carbon atoms in the parent chain). Refers to an alkenyl group further comprising (2, 3, or 4 heteroatoms) or located at one or more terminal positions (s) of the parent chain. In some embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“hetero C _{2 to 10} alkenyl”. "). In some embodiments, the heteroalkenyl group has 2-9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“hetero C _2-9 alkenyl”. ). In some embodiments, the heteroalkenyl group has 2-8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“hetero C _2-8 alkenyl”). ). In some embodiments, the heteroalkenyl group has 2-7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“hetero C _2-7 alkenyl”. ). In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“hetero C _2-6 alkenyl”. ). In some embodiments, the heteroalkenyl group has 2-5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain (“hetero C _2-5 alkenyl”). "). In some embodiments, the heteroalkenyl group has 2-4 carbon atoms, at least 1 double bond, and 1 or 2 heteroatoms in the parent chain (“hetero C _2-4 alkenyl”). "). In some embodiments, the heteroalkenyl group has 2-3 carbon atoms, at least one double bond, and 1 heteroatom in the parent chain (“hetero C _2-3 alkenyl”). .. In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain (“hetero C _2-6 alkenyl”). "). Unless so specified, each presence of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). .. In some embodiments, the heteroalkenyl group is an unsubstituted _{heteroC 2-10} alkenyl. In some embodiments, the heteroalkenyl group is a substituted _{heteroC 2-10} alkenyl.

The term "alkynyl" refers to a radical of a straight or branched hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (eg, 1, 2, 3, or 4). Triple bond) ("C _2-10 alkynyl"). In some embodiments, the alkynyl group has 2-9 carbon atoms (“C _2-9 alkynyl”). In some embodiments, the alkynyl group has 2-8 carbon atoms (“C _2-8 alkynyl”). In some embodiments, the alkynyl group has 2-7 carbon atoms (“C _2-7 alkynyl”). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C _{2 to 6} alkynyl”). In some embodiments, the alkynyl group has 2-5 carbon atoms (“C _2-5 alkynyl”). In some embodiments, the alkynyl group has 2-4 carbon atoms (“C _2-4 alkynyl”). In some embodiments, the alkynyl group has 2-3 carbon atoms (“C _2-3 alkynyl”). In some embodiments, the alkynyl group has two carbon atoms (“C ₂ alkynyl”). One or more carbon-carbon triple bonds can be present internally (such as 2-butynyl) or terminally (such as 1-butynyl). Examples of C _2-4 alkynyl groups are, but are not limited to, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C). ₄ ) etc. are included. Examples of C _2-6 alkenyl groups include the aforementioned C _2-4 alkynyl groups as well as pentynyl (C ₅ ), hexynyl (C ₆ ) and the like. Additional examples of alkynyl include heptinyl (C ₇ ), octynyl (C ₈ ) and the like. Unless so specified, each presence of an alkynyl group is independently unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C _2-10 alkynyl. In some embodiments, the alkynyl group is a substituted C _2-10 alkynyl.

The term "heteroalkynyl" refers to at least one heteroatom (eg, one) selected from oxygen, nitrogen, or sulfur within the parent chain (ie, inserted between adjacent carbon atoms in the parent chain). Refers to an alkynyl group that further comprises (2, 3, or 4 heteroatoms) or is located at the terminal position (s) of one or more parent chains. In some embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“hetero C _{2 to 10} alkynyl”). ). In some embodiments, the heteroalkynyl group has 2-9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“hetero C _2-9 alkynyl”). .. In some embodiments, the heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“hetero C _2-8 alkynyl”). .. In some embodiments, the heteroalkynyl group has 2-7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“hetero C _2-7 alkynyl”). .. In some embodiments, the heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“hetero C _2-6 alkynyl”). .. In some embodiments, the heteroalkynyl group has 2-5 carbon atoms, at least 1 triple bond, and 1 or 2 heteroatoms in the parent chain (“hetero C _2-5 alkynyl”). ). In some embodiments, the heteroalkynyl group has 2-4 carbon atoms, at least 1 triple bond, and 1 or 2 heteroatoms in the parent chain (“hetero C _2-4 alkynyl”). ). In some embodiments, the heteroalkynyl group has 2-3 carbon atoms, at least one triple bond, and 1 heteroatom in the parent chain (“hetero C _2-3 alkynyl”). In some embodiments, the heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain (“hetero C _2-6 alkynyl”). ). Unless otherwise specified, each presence of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). .. In some embodiments, the heteroalkynyl group is an unsubstituted _{heteroC 2-10} alkynyl. In some embodiments, the heteroalkynyl group is a substituted hetero C _2-10 alkynyl.

The term "carbocyclyl" or "carbon ring" refers _{to a non-aromatic cyclic hydrocarbon having 3 to 14} cyclic carbon atoms ("C 3 to 14 carbocyclyl") and 0 heteroatoms in a non-aromatic ring system. Refers to the radical of the group. In some embodiments, the carbocyclyl group has 3-10 cyclic carbon atoms (“C _3-10 carbocyclyl”). In some embodiments, the carbocyclyl group has 3-8 cyclic carbon atoms (“C _3-8 carbocyclyl”). In some embodiments, the carbocyclyl group has 3-7 cyclic carbon atoms (“C _3-7 carbocyclyl”). In some embodiments, the carbocyclyl group has 3 to 6 cyclic carbon atoms (“C _{3 to 6} carbocyclyl”). In some embodiments, the carbocyclyl group has 4-6 cyclic carbon atoms (“C _4-6 carbocyclyl”). In some embodiments, the carbocyclyl group has 5-6 cyclic carbon atoms (“C _5-6 carbocyclyl”). In some embodiments, the carbocyclyl group has 5-10 cyclic carbon atoms (“C _5-10 carbocyclyl”). Illustrated C _3-6 carbocyclyl groups include, but are not limited to, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl ( Includes C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ) and the like. _{C 3 to 8} carbocyclyl group exemplified, without limitation, the foregoing _{C 3 to 6} carbocyclyl groups as well as cycloheptyl to cyclo _(C 7), cycloheptenyl _(C 7), Putajieniru cyclohexane _(C 7), Putatorieniru cyclohexane ( C _7), cyclooctyl _(C 8), cyclooctenyl _(C 8), bicyclo [2.2.1] heptanyl _(C 7), bicyclo [2.2.2] octanyl _{(C 8)} or the like. The exemplary C _3-10 carbocyclyl groups include, without limitation, the aforementioned C _3-8 carbocyclyl groups as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), _{cyclodecenyl (C 10} ), octahydro-. 1H-indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro [4.5] decanyl (C ₁₀ ) and the like are included. In some embodiments, the carbocyclyl group is monocyclic (“monocyclic carbocyclyl”) or polycyclic (eg, bicyclic (eg, “bicyclic carbocyclyl”) or tricyclic, as the above example illustrates. Either a system (containing a fused ring system, a bridged ring system or a spiro ring system), such as a "tricyclic carbocyclyl"), saturated or one or more carbon-carbon double bonds or May contain triple bonds. "Carbocyclyl" also means that the carbocyclyl ring has an attachment point on the carbocyclyl ring, as defined above, in which case the number of carbons continues to specify the number of carbons in the carbocyclic system. It also includes a ring system fused with the above aryl or heteroaryl group. Unless so specified, each presence of a carbocyclyl group is independently unsubstituted (“unsubstituted carbocyclyl”) or substituted with one or more substituents (“substituted carbocyclyl”). In some embodiments, the carbocyclyl group is an unsubstituted C _3-14 carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C _3-14 carbocyclyl.

In some embodiments, the "carbocyclyl" is a monocyclic, saturated carbocyclyl group having 3-14 cyclic carbon atoms ("C _3-14 cycloalkyl"). In some embodiments, the cycloalkyl group has 3-10 cyclic carbon atoms (“C _3-10 cycloalkyl”). In some embodiments, the cycloalkyl group has 3-8 cyclic carbon atoms (“C _3-8 cycloalkyl”). In some embodiments, the cycloalkyl group has 3-6 cyclic carbon atoms (“C _3-6 cycloalkyl”). In some embodiments, the cycloalkyl group has 4-6 cyclic carbon atoms (“C _4-6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5-6 cyclic carbon atoms (“C _5-6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5-10 cyclic carbon atoms (“C _5-10 cycloalkyl”). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of C _3-6 cycloalkyl groups include the aforementioned C _5-6 cycloalkyl groups as well as cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C _3-8 cycloalkyl groups include the aforementioned C _3-6 cycloalkyl groups as well as cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise specified, each presence of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). .. In some embodiments, the cycloalkyl group is an unsubstituted C _3-14 cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C _3-14 cycloalkyl.

The term "heterocyclyl" or "heterocyclic" has a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Refers to 3-14 membered non-aromatic ring radicals ("3-14 membered heterocyclyl"). For heterocyclyl groups containing one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom, as the valence allows. Heterocyclyl groups are fused, such as monocyclic (“monocyclic carbocyclyl”) or polycyclic (eg, bicyclic (“bicyclic carbocyclyl”) or tricyclic (“tricyclic carbocyclyl”). It contains a ring system, a crosslinked ring system or a spiro ring system)) and can be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" is also where the heterocyclyl ring is fused with one or more carbocyclyl groups, as defined above, where the attachment point is on either the carbocyclyl or the heterocyclyl ring or the ring system. Here, the heterocyclyl ring is fused with one or more aryl groups or heteroaryl rings, as defined above, where the attachment point is on the heterocyclyl ring, in which case the number of ring members is: Includes a ring system that continues to specify the number of ring members in the heterocyclyl ring system. Unless so specified, each presence of heterocyclyl is independently unsubstituted (“unsubstituted heterocyclyl”) or substituted with one or more substituents (“substituted heterocyclyl”). In some embodiments, the heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3-14 member heterocyclyl.

In some embodiments, the heterocyclyl group has a cyclic carbon atom and 1 to 4 cyclic heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur, 5-5. It is a 10-membered non-aromatic ring system (“5-10-membered heterocyclyl”). In some embodiments, the heterocyclyl group has a cyclic carbon atom and 1 to 4 cyclic heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur, 5-5. It is an 8-membered non-aromatic ring system ("5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group has a cyclic carbon atom and 1 to 4 cyclic heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur, 5-5. It is a 6-membered non-aromatic ring system (“5-6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

The exemplified, three-membered heterocyclyl group containing one heteroatom includes, but is not limited to, aziridinyl, oxylanyl, and tiylanyl. An exemplary, four-membered heterocyclyl group containing a single heteroatom includes, but is not limited to, azetidinyl, oxetanyl, and thietanyl. The exemplary 5-membered heterocyclyl group containing one heteroatom is, but is not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolill, and pyrrolyl-2,5. -Includes Zeon. An exemplary 5-membered heterocyclyl group containing two heteroatoms includes, but is not limited to, dioxolanyl, oxathiolanyl and dithiolanyl. The exemplary 5-membered heterocyclyl group containing 3 heteroatoms includes, but is not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. An exemplary 6-membered heterocyclyl group containing a single heteroatom includes, but is not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. The exemplary 6-membered heterocyclyl group containing 2 heteroatoms includes, but is not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. The exemplary 6-membered heterocyclyl group containing 3 heteroatoms comprises, but is not limited to, triazinyl. An exemplary, 7-membered heterocyclyl group containing a single heteroatom includes, but is not limited to, azepanyl, oxepanyl and thiepanyl. An exemplary 8-membered heterocyclyl group containing a heteroatom includes, but is not limited to, azocanyl, oxecanyl and thiocanyl. Illustrated bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindrill, tetrahydroquinolinyl, tetrahydroisoquinolinyl. , Decahydroquinolinyl, Decahydroisoquinolinyl, Octahydrochromenyl, Octahydroisochromenyl, Decahydronaphthylidineyl, Decahydro-1,8-naphthylidineyl, Octahydropyrrole [3,2-b] pyrrole, Indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo [e] [1,4] diazepinyl, 1,4,5,7-tetrahydropyrano [3,4-b] pyrrole, 5,6-dihydro-4H -Flo [3,2-b] pyrrole, 6,7-dihydro-5H-Flo [3,2-b] pyranyl, 5,7-dihydro-4H-thieno [2,3-c] pyranyl, 2,3 -Dihydro-1H-pyrrolo [2,3-b] pyridinyl, 2,3-dihydroflo [2,3-b] pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo [2,3-b] pyridinyl , 4,5,6,7-Tetrahydroflo [3,2-c] pyridinyl, 4,5,6,7-tetrahydrothieno [3,2-b] pyridinyl, 1,2,3,4-tetrahydro-1 , 6-Naftyridinyl and the like.

The term "aryl", as long as it is provided in an aromatic ring system, is monocyclic or polycyclic (eg, bicyclic or tricyclic) with 6-14 cyclic carbon atoms and 0 heteroatoms. ) Refers to radicals of a 4n + 2 aromatic ring system (eg, having 6, 10, or 14 Π electron sharing in a cyclic array) (“C _6-14 aryl”). In some embodiments, the aryl group has 6 cyclic carbon atoms (“C ₆ aryl”; eg, phenyl). In some embodiments, the aryl group has 10 cyclic carbon atoms (“C ₁₀ aryl”; for example, naphthyls such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has a 14 cyclic carbon atom (“C ₁₄ aryl”; for example, anthracyl). "Aryl" is also where the aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the radical or non-adhesion is on the aryl ring, such In some cases, the number of carbon atoms comprises a ring system that continues to specify the number of carbon atoms in the aryl ring system. Unless so specified, each presence of an aryl group is independently unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted aryl”). In some embodiments, the aryl group is an unsubstituted C _6-14 aryl. In some embodiments, the aryl group is a substituted C _6-14 aryl.

The term "heteroaryl" has cyclic carbon atoms and 1 to 4 cyclic heteroatoms as long as they are provided in the aromatic ring system, where each heteroatom is independently derived from nitrogen, oxygen, and sulfur. Selected 5- to 14-membered monocyclic or polycyclic (eg, bicyclic, tricyclic) 4n + 2 aromatic ring system (eg, 6, 10, or 14 Π electron sharing in a cyclic array) (Has) radicals ("5-14 membered heteroaryl"). For heteroaryl groups containing one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom, as the valence allows. Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" is where the heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the attachment point is on the heteroaryl ring, in such cases. Includes a ring system in which the number of ring members continues to specify the number of ring members in the heteroaryl ring system. A "heteroaryl" is also where the heteroaryl ring is fused with one or more aryl groups, as defined above, where the attachment point is on either the aryl or the heteroaryl ring. In such cases, the number of ring members comprises a ring system in which the number of ring members continues to specify the number of ring members in the condensed polycyclic (aryl / heteroaryl) ring system. A polycyclic heteroaryl group, wherein one ring does not contain a heteroatom (eg, indolyl, quinolinyl, carbazolyl, etc.) and has an attachment point on any of the rings, i.e. any of the rings having a heteroatom. It is possible (eg, 2-indrill), or the ring does not contain a heteroatom (eg, 5-indrill).

In some embodiments, the heteroaryl group has a cyclic carbon atom and 1 to 4 cyclic heteroatoms as long as provided in the aromatic ring system, where each heteroatom is independently nitrogen, oxygen. , And a 5- to 10-membered aromatic ring system selected from sulfur ("5-10-membered heteroaryl"). In some embodiments, the heteroaryl group has a cyclic carbon atom and 1 to 4 cyclic heteroatoms as long as provided in the aromatic ring system, where each heteroatom is independently nitrogen, oxygen. , And a 5-8 membered aromatic ring system selected from sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group has a cyclic carbon atom and 1 to 4 cyclic heteroatoms as long as provided in the aromatic ring system, where each heteroatom is independently nitrogen, oxygen. , And a 5-6 membered aromatic ring system selected from sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has a monocyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless so specified, each presence of a heteroaryl group is independently unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). .. In some embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

The exemplary 5-membered heteroaryl group containing one heteroatom is, but is not limited to, pyrrolyl, furanyl, and thiophenyl. The exemplified, 5-membered heteroaryl group containing two heteroatoms is, without limitation, imidazolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, and isothiazolyl. The exemplary 5-membered heteroaryl group containing 3 heteroatoms is, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. The exemplary 5-membered heteroaryl group containing 4 heteroatoms is, without limitation, tetrazolyl. The exemplary 6-membered heteroaryl group containing one heteroatom is, without limitation, pyridinyl. The exemplary 6-membered heteroaryl group containing 2 heteroatoms is, without limitation, pyridadinyl, pyrimidinyl, and pyrazineyl. The exemplary 6-membered heteroaryl group containing 3 or 4 heteroatoms is, without limitation, triazinyl and tetradinyl, respectively. The exemplary 7-membered heteroaryl group containing one heteroatom is, without limitation, azepinyl, oxepynyl, and thiepinyl. Exemplified 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindrill, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxa. Includes zoryl, benzisooxazolyl, benzooxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiasiazolyl, indridinyl, and prynyl. Illustrated 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyldinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Illustrated tricyclic heteroaryl groups include, but are not limited to, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxadinyl, and phenazinyl.

Adding the suffix "-ene" to the base means that the group is a divalent moiety, for example, alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene. Is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, Carbocyclylene is the divalent portion of carbocyclyl, heterocyclylene is the divalent portion of heterocyclyl, arylene is the divalent portion of aryl, and heteroarylene is the divalent portion of heteroaryl. ..

The groups may be optionally substituted unless expressly specified otherwise. The term "arbitrarily replaced" refers to being replaced or not replaced. In some embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Arbitrarily substituted" is a group that may be substituted or unsubstituted (eg, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "Substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroalkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" Refers to carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted" means that at least one hydrogen present on the group is an acceptable substituent, eg, a compound in which the substitution is stable, eg, rearrangement, cyclization, elimination, or. It means that it is replaced with a substituent, which results in a compound that is not subject to spontaneous conversion due to other reactions or the like. Unless otherwise indicated, a "substituent" group has a substituent at one or more substitutable positions of the group, and if more than one position of any given structure is substituted, the substituent is at each position. Is the same or different. The term "substituted" includes any of the substituents described herein that are intended to include substitutions of organic compounds with all acceptable substituents, resulting in the formation of stable compounds. The present invention contemplates any such combination in order to reach a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen have any suitable substituents described herein that satisfy the valences of hydrogen substituents and / or heteroatoms, resulting in the formation of stable moieties. You may be doing it. The present invention is not intended to be limited in any manner by the exemplary substituents described herein.

Illustrated carbon atom substituents are, but are not limited to, halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON (R ^bb ). ^{_{2, -N (R bb) 2}} , -N (R bb) 3 + X -, -N (OR cc) R bb, -SH, -SR aa, -SSR cc, -C (= O) R aa, -CO ₂ H, -CHO, -C (OR ^cc ) ₃ , -CO ₂ R ^aa , -OC (= O) R ^aa , -OCO ₂ R ^aa , -C (= O) N (R ^bb ) ₂ , -OC (= O) N (R ^bb ) ₂ , -NR ^bb C (= O) R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C (= O) N (R ^bb ) ₂ , -C ( = NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , -OC (= NR ^bb ) R ^aa , -OC (= NR ^bb ) OR ^aa , -C (= NR ^bb ) N (R ^bb ) ₂ , -OC (= NR ^bb ) N (R ^bb ) ₂ , -NR ^bb C (= NR ^bb ) N (R ^bb ) ₂ , -C (= O) NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N (R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S (= O) R ^aa , -OS (= O) R ^aa , -Si (R ^aa ) ₃ , -OSi (R ^aa ) _3- C (= S) N (R ^bb ) ₂ , -C (= O) SR ^aa , -C (= S) SR ^aa , -SC (= S) SR ^aa , -SC (= O) SR ^aa , -OC (= O) SR ^aa , -SC (= O) OR ^aa , -SC (= O) R ^aa , -P (= O) (R ^aa ) ₂ , -P (= O) (OR ^cc ) ₂ , -OP (= O) (R ^aa ) ₂ , -OP (= O) (OR ^cc ) ₂ , -P (= O) (N (R ^bb ) ₂ ) ₂ , -OP (= O) (N (R ^bb ) ₂ ) ₂ , -NR ^bb P (= O) (R ^aa ) ₂ , -NR ^bb P (= O) (OR ^cc ) ₂ , -NR ^{bb _{P (= O) (N (}} R bb) 2) 2, -P (R cc) 2, -P (OR cc) 2, -P (R cc) 3 + X -, -P (OR cc) 3 + X ^{_{-, -P (R cc) 4}} , -P (OR cc) 4, -OP (R cc) 2, -OP (R cc) 3 + X -, -OP (OR cc) 2, -OP (OR cc ^{_{) 3 + X -, -OP (}} R cc) 4, -OP (OR cc) 4, -B (R aa) 2, -B (OR cc) 2, -BR aa (OR cc), C 1~10 Alkyl, C _1-10 perhaloalkyl, C _2-10 alkynyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10 alkenyl, hetero C _2-10 alkynyl, C _3-10 carbocyclyl, 3 ~ Includes 14-membered heterocyclyl, C _6-14 aryl, and 5-14 member heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl , Independently substituted with 0, 1, 2, 3, 4, or 5R ^dd groups; where X ⁻ is a counter ion;
Alternatively, the two genomic hydrogens on the carbon atom are groups = O, = S, = NN (R ^bb ) ₂ , = NNR ^bb C (= O) R ^aa , = NNR ^bb C (= O) OR ^aa , = NNR ^bb S (= O) ₂ R ^aa , = NR ^bb , or = NOR ^cc replaced;
Each presence of ^Raa _{independently has C 1-10} alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10 alkenyl, heteroaryl _{C 2 to 10 alkynyl, C 3 to 10} carbocyclyl, 3-14 membered _{heterocyclyl,} or is selected from heteroaryl _{C having 6 to 14} aryl, and 5-14 membered, or two ^{R aa} groups linked Form a 3,-14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independent. And have been substituted with 0, 1, 2, 3, 4, or 5R ^{dd groups;}
Each presence of R ^bb independently has hydrogen, -OH, -OR ^aa , -N (R ^cc ) ₂ , -CN, -C (= O) R ^aa , -C (= O) N (R ^cc). ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , -SO ₂ N (R ^cc ) ₂ ,- SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc , -C (= S) SR ^cc , -P (= O) (R ^aa ) ₂ , -P (= O) (OR ^cc ) ₂ , -P (= O) (N (R ^cc ) ₂ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _{2 to 10} alkenyl, C _{2 to 10} alkynyl, hetero C _{1 to 10} alkyl, hetero C _{2 to 10} alkenyl, hetero C _{2 to 10} alkynyl, C _{3 to 10} carbocyclyl, 3 to 14 member heterocyclyl, C _{6 to 14} aryl , and 5-14 membered either heteroaryl, or two ^{R bb} groups linked, form a heteroaryl ring having 3 to 14-membered heterocyclyl or 5-14 membered, wherein each alkyl, Alkynes, alkynyls, heteroalkyls, heteroalkenyls, heteroalkynyls, carbocyclyls, heterocyclyls, aryls, and heteroaryls are independently ^{substituted with 0, 1, 2, 3, 4, or 5R dd} groups; where X ^- is a counterion;
Each presence of R ^cc is independent of hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10. alkenyl, hetero _{C 2 to 10 alkynyl, C 3 to 10} carbocyclyl, 3-14 membered _{heterocyclyl, C having 6 to 14} aryl, and 5-14 membered either heteroaryl, or two ^{R cc} groups linked To form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl , Independently substituted with 0, 1, 2, 3, 4, or 5R ^{dd groups;}
Each presence of R ^dd independently has halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON (R ^ff ) ₂ ,- ^{_{N (R ff) 2, -N}} (R ff) 3 + X -, -N (OR ee) R ff, -SH, -SR ee, -SSR ee, -C (= O) R ee, -CO 2 H, -CO ₂ R ^ee , -OC (= O) R ^ee , -OCO ₂ R ^ee , -C (= O) N (R ^ff ) ₂ , -OC (= O) N (R ^ff ) ₂ ,- NR ^ff C (= O) R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C (= O) N (R ^ff ) ₂ , -C (= NR ^ff ) OR ^ee , -OC (= NR ^ff ) R ^ee , -OC (= NR ^ff ) OR ^ee , -C (= NR ^ff ) N (R ^ff ) ₂ , -OC (= NR ^ff ) N (R ^ff ) ₂ , -NR ^ff C (= NR ^ff ) N (R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N (R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S (= O) R ^ee , -Si ( ^Ree ) ₃ , -OSi ( ^Ree ) ₃ , -C (= S) N (R ^ff ) ₂ , -C (= O) SR ^ee , -C (= S) SR ^ee ,- SC (= S) SR ^ee , -P (= O) (OR ^ee ) ₂ , -P (= O) ( ^Ree ) ₂ , -OP (= O) ( ^Ree ) ₂ , -OP (= O) (OR ^ee ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6 alkenyl, hetero C _2-6 Alkinyl, C _3-10 carbocyclyl, 3-10 member heterocyclyl, C _6-10 aryl, 5-10 member heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, Carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two geminal R ^dd substituents are linked and = O or = S can be formed; where X ⁻ is a counterion;
Each presence of ^Ree _{independently has C 1-6} alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6 alkenyl, Hetero C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 member heterocyclyl, and 3-10 member heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, Heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with ^{0, 1, 2, 3, 4, or 5R gg groups;}
Each presence of R ^ff independently includes hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6. Selected from alkenyl, hetero C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 member heterocyclyl, C _6-10 aryl and 5-10 member heteroaryl, or two R ^ff groups are linked. To form a 3-10 membered heterocyclyl or a 5-10 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl Independently substituted with 0, 1, 2, 3, 4, or 5R ^gg groups; and ^{each presence of R gg} is independently halogen, -CN, -NO ₂ , -N ₃ , -. SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ₂ , -N (C _1-6 alkyl) ^{_{3 + X -, -NH (C}} 1~6 ^{_{alkyl) 2 + X -, -NH 2}} (C 1~6 ^{_{alkyl) + X -, -NH 3 +}} X -, -N (OC 1~6 alkyl) ( C _1-6 alkyl), -N (OH) (C _1-6 alkyl), -NH (OH), -SH _{, -SC 1-6} alkyl, -SS (C _1-6 alkyl), -C (= O) (C _1-6 alkyl), _{-CO 2} H, -CO ₂ (C _1-6 alkyl), -OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl) , -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH (C _1-6 alkyl), -NHC (= O) (C _{1) ~ 6} alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC (= O) N (C _{1-6) Alkyne 2} , -NHC (= O) NH (C _1-6 alkyl), -NHC (= O) NH ₂ , -C (= NH) O (C _1-6 alkyl), -OC (= NH) ( C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -C (= NH) N (C _1-6 alkyl) ₂ , -C (= NH) NH (C _1-6 alkyl), -C (= NH) NH ₂ , -OC (= NH) N (C _1-6 alkyl) ₂ , -OC (= NH) NH (C _1-6 alkyl), -OC (= NH) NH ₂ , -NHC (= NH) N (C _1-6 alkyl) ₂ ,- NHC (= NH) NH ₂ , -NHSO ₂ (C _{1 to 6} alkyl), -SO ₂ N (C _{1 to 6} alkyl) ₂ , -SO ₂ NH (C _{1 to 6} alkyl), -SO ₂ NH ₂ , -SO ₂ (C _{1 to 6} alkyl), -SO ₂ O (C _{1 to 6} alkyl), -OSO ₂ (C _{1 to 6} alkyl), -SO (C _{1 to 6} alkyl), -Si (C _{1 to 6 alkyl) 6} Alkyne) ₃ , -OSi (C _1-6 Alkyne) _3- C (= S) N (C _1-6 Alkyne) ₂ , C (= S) NH (C _1-6 Alkyne), C (= S) NH ₂ , -C (= O) S (C _{1 to 6} alkyl), -C (= S) SC _{1 to 6} alkyl, -SC (= S) SC _{1 to 6} alkyl, -P (= O) (OC) _1-6 alkyl) ₂ , -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6 alkenyl, hetero C _2-6 alkynyl, C _{3 Is it 10} carbocyclyl, C _6-10 aryl, 3-10 member heterocyclyl, 5-10 member heteroaryl; or the two Geminal ^Rgg substituents are linked to form = O or = S. Obtained; where X ⁻ is a counter ion.

In some embodiments, the substituents are halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON (C _1-6 alkyl). _2, -N _{(C 1~6 alkyl) 2,} -N _(C 1~6 ^{_{alkyl) 3 + X -, -NH (}} C 1~6 ^{_{alkyl) 2 + X -, -NH 2}} (C 1~6 alkyl ^{_{) + X -, -NH 3 +}} X -, -N (OC 1~6 _{alkyl) (C 1 to 6 alkyl), - N (OH) (} C 1~6 alkyl), - NH (OH), - SH , _{-SC 1 to 6} alkyl, -SS _{(C 1 to 6 alkyl), - C (= O)} (C 1~6 _{alkyl), - CO 2 H, -CO} 2 (C 1~6 alkyl), - OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH ₂ , -C (= O) N (C _1-6 alkyl) ₂ , -OC (= O) NH (C _1-6 alkyl), -NHC (= O) (C _1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C _1-6 alkyl),- NHCO ₂ (C _1-6 alkyl), -NHC (= O) N (C _1-6 alkyl) ₂ , -NHC (= O) NH (C _1-6 alkyl), -NHC (= O) NH ₂ , -C (= NH) O (C _1-6 alkyl), -OC (= NH) (C _1-6 alkyl), -OC (= NH) OC _1-6 alkyl, -C (= NH) N (C) _1-6 alkyl) ₂ , -C (= NH) NH (C _1-6 alkyl), -C (= NH) NH ₂ , -OC (= NH) N (C _1-6 alkyl) ₂ , -OC ( = NH) NH (C _1-6 alkyl), -OC (= NH) NH ₂ , -NHC (= NH) N (C _1-6 alkyl) ₂ , -NHC (= NH) NH ₂ , -NHSO ₂ ( C _{1 to 6 alkyl), - SO 2 N (C} 1~6 _{alkyl) 2, -SO 2 NH (C} 1~6 _{alkyl), - SO 2 NH 2,} -SO 2 (C 1~6 alkyl), - _{SO 2} O _(C 1~6 _alkyl), - OSO _{2 (C 1~6 alkyl),} - SO _(C 1~6 _alkyl), - Si _{(C 1~6 alkyl) 3,} -OSi _{(C 1~6} Alkyl) _3- C (= S) N (C _1-6 alkyl) ₂ , C (= S) NH (C _1-6 alkyl), C (= S) NH ₂ , -C (= O) S (C) _1-6 Alkyne), -C (= S) SC _1-6 alkyl, -SC (= S) SC _1-6 alkyl, -P (= O) (OC _1-6 alkyl) ₂ , -P (= O) (C _1-6 alkyl) ₂ , -OP (= O) (C _1-6 alkyl) ₂ , -OP (= O) (OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkynyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6 alkynyl, hetero C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 members Heterocyclyls may contain 5- to 10-membered heteroaryls; or two geminal hydrogens may be linked to form = O or = S; where X ⁻ is a counterion.

The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodine, -I).

The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxyl" is by extension
Refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, -OR ^aa , -ON (R ^bb ) ₂ , -OC (= O) SR ^aa , -OC ( = O) R ^aa , -OCO ₂ R ^aa , -OC (= O) N (R ^bb ) ₂ , -OC (= NR ^bb ) R ^aa , -OC (= NR ^bb ) OR ^aa , -OC (= NR) _{^{bb) N (R bb) 2}} , -OS (= O) R aa, -OSO 2 R aa, -OSi (R aa) 3, -OP (R cc) 2, -OP (R cc) 3 + X - _{^{, -OP (oR cc) 2,}} -OP (oR cc) 3 + X -, -OP (= O) (R aa) 2, -OP (= O) (oR cc) 2, and -OP (= O ) (N (R ^bb ) ₂ ) Containing groups selected from ₂ ^{, where X −} , R ^aa , R ^bb , and R ^cc are as defined herein.

The term "amino" refers to _{the group -NH 2.} The term "substituted amino", by extension, refers to mono-substituted amino, di-substituted amino, or tri-substituted amino. In some embodiments, the "substituted amino" is a mono- or di-substituted amino group.

The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, -NH (R ^bb ), -NHC (=). O) R ^aa , -NHCO ₂ R ^aa , -NHC (= O) N (R ^bb ) ₂ , -NHC (= NR ^bb ) N (R ^bb ) ₂ , -NHSO ₂ R ^aa , -NHP (= O) Contains groups selected from (OR ^cc ) ₂ and -NHP (= O) (N (R ^bb ) ₂ ) ₂ ^{, where R aa} , R ^bb and R ^cc are as defined herein. in and, ^{R bb} group -NH ^{(R bb)} it is not hydrogen.

The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, -N (R ^bb ) ₂ , -NR ^bb C (= O). ) R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C (= O) N (R ^bb ) ₂ , -NR ^bb C (= NR ^bb ) N (R ^bb ) ₂ , -NR ^bb SO ₂ R ^aa , -NR ^bb P (= O) (OR ^cc ) ₂ , and -NR ^bb P (= O) (N (R ^bb ) ₂ ) ₂ containing groups selected from here, R ^aa , R ^bb and ^Rcc is as defined herein, provided that the nitrogen atom directly attached to the parent molecule is not replaced by hydrogen.

The term "trisubstituted amino" refers to amino groups wherein the nitrogen atom which is attached directly to the parent molecule is replaced by three groups, ^{-N (R} _{bb) 3} and _{^{-N (R bb) 3 + X}} - ^Containing groups selected from, where R bb and X ⁻ are as defined herein.

The term "sulfonyl" refers to a group selected from _{-SO 2} N (R ^bb ) ₂ , -SO ₂ R ^aa , and -SO ₂ OR ^{aa , where R aa} and R ^bb are herein. As defined.

The term "sulfinyl" refers to a group selected from the group -S (= O) R ^{aa , where R aa} is as defined herein.

The term "acyl" is used in the general formulas -C (= O) R ^X1 , -C (= O) OR ^X1 , -C (= O) -OC (= O) R ^X1 , -C (= O) SR. ^X1 , -C (= O) N ( ^RX1 ) ₂ , -C (= S) R ^X1 , -C (= S) N ( ^RX1 ) ₂ , -C (= S) O ( ^RX1 ),- C (= S) S ( ^RX1 ), -C (= NR ^X1 ) R ^X1 , -C (= NR ^X1 ) OR ^X1 , -C (= NR ^X1 ) SR ^X1 , and -C (= NR ^X1 ) N ( ^RX1 ) Refers to a group having ₂ ^{where RX1} is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, ring. Formal or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or non-branched heteroaliphatic; Cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or Unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphatic oxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, fat Aliphaticthioxy, heteroaliphaticthioxy, alkyltioxy, heteroalkyltioxy, aryltioxy, heteroaryltioxy, mono- or di-increasingamino, mono-or di-hydrophaticamino, mono-or In mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino. Is there; or the two ^RX1 groups together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acid _(-CO 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Aryl substituents are, but are not limited to, any of the substituents described herein that result in the formation of stable moieties (eg, aliphatic, alkyl, alkenyl, alkynyl, heteroalitty, heterocyclic, Aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azide, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroaryl Amino, alkylaryl, arylalkyl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic tioxy, heteroaliphatic tioxy, alkyltioxy, heteroalkyltioxy, aryltioxy , Heteroaryltioxy, acyloxy, etc. (each of which may or may not be further substituted).

The term "carbonyl" refers to a group in which the carbon atom directly attached to the parent molecule is sp ² hybrid and is substituted with an oxygen, nitrogen or sulfur atom, eg, a ketone (eg, -C). (= O) R ^aa ), carboxylic acid (eg -CO ₂ H), aldehyde (-CHO), ester (eg -CO ₂ R ^aa , -C (= O) SR ^aa , -C (=) S) SR ^aa ), amide (for example, -C (= O) N (R ^bb ) ₂ , -C (= O) NR ^bb SO ₂ R ^aa , -C (= S) N (R ^bb ) ₂ ) , And imine (eg, -C (= NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa ), -C (= NR ^bb ) N (R ^bb ) ₂ ). Here, R ^aa and R ^bb are as defined herein.

The term "silyl" refers to the group -Si (R ^aa ) ₃ , where R ^aa is as defined herein.

The term "oxo" refers to group = O and the term "thiooxo" refers to group = S.

Nitrogen atoms can be substituted or unsubstituted, as the valence allows, and can include primary, secondary, tertiary, and quaternary nitrogen atoms. Illustrated nitrogen atom substituents are, but are not limited to, hydrogen, -OH, -OR ^aa , -N (R ^cc ) ₂ , -CN, -C (= O) R ^aa , -C (= O) N. (R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^bb ) R ^aa , -C (= NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , -SO ₂ N (R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc , -C (= S) SR ^cc , -P (= O) (OR ^cc ) ₂ , -P (= O) ( ^Raa ) ₂ , -P (= O) (N (R ^cc ) ₂ ) ₂ , C _1-10 Alkyne, C _1-10 Perhaloalkyl, C _2-10 Alkyne, C _2-10 Alkynyl, Hetero C _1-10 Alkyne, Hetero C _2-10 Alkyne, Hetero C _2-10 Alkyne, C _3-10 Carbocyclyl , 3-14 membered _{heterocyclyl, C having 6 to 14} aryl, and 5-14 membered two ^{R cc} group attached either including heteroaryl, or N atom is linked, the 3-14 membered Heterocyclyls or 5- to 14-membered heteroaryl rings are formed, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently 0, 1 Substituted with 2, 3, 4, or 5 R ^dd groups, R ^aa , R ^bb , R ^cc and R ^dd are as defined above.

In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protective groups are not limited to these, but are limited to -OH, -OR ^aa , -N (R ^cc ) ₂ , -C (= O) R ^aa , -C (= O) N (R ^cc ) ₂ , -CO. ₂ R ^aa , -SO ₂ R ^aa , -C (= NR ^cc ) R ^aa , -C (= NR ^cc ) OR ^aa , -C (= NR ^cc ) N (R ^cc ) ₂ , -SO ₂ N (R) ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C (= S) N (R ^cc ) ₂ , -C (= O) SR ^cc , -C (= S) SR ^cc , C _1-10 alkyl (eg, aralkyl, heteroaralkyl), C _2-10 alkynyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10 alkenyl, hetero C _2-10 alkynyl, C _3-10 carbocyclyls, 3-14 membered heterocyclyls, C _6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, Heterocyclyls, alkynes, aryls, and heteroaryls are independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, with R ^aa , R ^bb , R ^cc and R ^dd. , As defined herein. Nitrogen protecting groups are well known in the art, Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, John Wiley & Sons, 1999 ( herein incorporated by reference) to be described in detail Including things.

For example, nitrogen-protecting groups such as amide groups (eg, -C (= O) ^Raa ) are not limited to these, but formamide, acetamido, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenyl. Propanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitphenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino) ) Acetamide, 3- (p-hydroxyphenyl) propanamide, 3- (o-nitrophenyl) propanamide, 2-methyl-2- (o-nitrophenoxy) propanamide, 2-methyl-2- (o-phenyl) Azophenoxy) Includes propanamide, 4-chlorobutaneamide, 3-methyl-3-nitrobutaneamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl) benzamide.

(As an ^{example, -C (= O) OR aa} ) carbamate group nitrogen protecting group, such as, but not limited to, methylcarbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-Sulfo) Fluorenylmethylcarbamate, 9- (2,7-dibromo) fluoroenylmethylcarbamate, 2,7-di-t-butyl- [9- (10,10-dioxo-10,10) , 10,10-Tetrahydrothioxanthyl)] Methyl carbamate (DBD-Tmoc), 4-methoxyphenacil carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate Mart (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1- Dimethyl-2,2-dibromoethylcarbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-methyl-1- (4-biphenylyl) ethyl Carbamate (Bpoc), 1- (3,5-di-t-butylphenyl) -1-methylethyl carbamate (t-Bumeoc), 2- (2'-and 4'-pyridyl) ethyl carbamate (Pyoc) ), 2- (N, N-dicyclohexylcarboxamid) ethylcarbamate, t-butylcarbamate (BOC or Boc), 1-adamantylcarbamate (Adoc), vinylcarbamate (Voc), allylcarbamate (Allloc), 1-Isopropylallyl carbamate (Ipaoc), cinnamylcarbamate (Coc), 4-nitrocinnamylcarbamate (Noc), 8-quinolylcarbamate, N-hydroxypiperidinylcarbamate, alkyldithiocarbamate, Benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitbenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methyl Sulfinylbenzylcarbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2- (p-toluenesulfonyl) ethi Lucarbamate, [2- (1,3-dithianyl)] methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p- (dihydroxyboryl) benzylcarbamate, 5-Benzisooxazolylmethylcarbamate, 2- (trifluoromethyl) -6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzyl Carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate Mart, Cyclohexylcarbamate, Cyclopentylcarbamate, Cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o- (N, N-dimethylcarboxamide) benzylcarbamate, 1, 1-Dimethyl-3- (N, N-dimethylcarboxamid) propylcarbamate, 1,1-dimethylpropynylcarbamate, di (2-pyridyl) methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate Mart, isobornylcarbamate, isobutylcarbamate, isonicotynylcarbamate, p- (p'-methoxyphenylazo) benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl -1-Cyclopropylmethylcarbamate, 1-methyl-1- (3,5-dimethoxyphenyl) ethylcarbamate, 1-methyl-1- (p-phenylazophenyl) ethylcarbamate, 1-methyl-1- Phenylethylcarbamate, 1-methyl-1- (4-pyridyl) ethylcarbamate, phenylcarbamate, p- (phenylazo) benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4- (Trimethylammonium) benzyl carbamate, and 2,4,6-trime Includes tylbenzylcarbamate.

Nitrogen-protecting groups such as sulfonamide groups (eg, -S (= O) ₂ ^Raa ) are, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl. -4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6- Tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide ( iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracene sulfonamide, 4- Includes (4', 8'-dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen-protecting groups include, but are not limited to, phenothiazinyl- (10) -acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-Acetylmethionine derivative, 4,5-diphenyl-3-oxazoline-2-one, N-phthalimide, N-dithiascusinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole , N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-Dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N- [2- (trimethylsilyl) Ethoxy] Methylamine (SEM), N-3-acetoxypropylamine, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl) amine, quaternary ammonium salt, N-benzylamine , N-di (4-methoxyphenyl) methylamine, N-5-dibenzosverylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl) diphenylmethyl] amine (MMTr), N- 9-Phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picorylamino N'-oxide, N-1 , 1-Dimethylthiomethyleneamine, N-benzylenemine, Np-methoxybenzylenemine, N-diphenylmethyleneamine, N-[(2-pyridyl) mesityl] methyleneamine, N- (N', N'-dimethyl Aminomethylene) amine, N, N'-isopropyridenediamine, Np-nitrobenzilidenamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N- (5-chloro-2-hydroxyphenyl) ) Phenylmethyleneamine, N-cyclohexylideneamine, N- (5,5-dimethyl-3-oxo-1-cyclohexenyl) amine, N-boran derivative, N-diphenylboric acid derivative, N- [phenyl (penta) Acylchrome-or tungsten) acyl] amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, a Min N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkylphosphoroamidate, dibenzylsholoamidate, diphenylshoroamidate, benzenesulfenamide Amide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3- Includes nitropyridine sulfenamide (Npys). In some embodiments, the nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, Acetyl (Ac), Benoxyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), Triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), trifuryl (Tf), or dansyl (Ds).

In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protective groups are not limited to these, but are limited to -R ^aa , -N (R ^bb ) ₂ , -C (= O) SR ^aa , -C (= O) R ^aa , -CO ₂ R ^aa , -C ( = O) N (R ^bb ) ₂ , -C (= NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , -C (= NR ^bb ) N (R ^bb ) ₂ , -S (= O) _{^{R aa, -SO 2 R aa,}} -Si (R aa) 3, -P (R cc) 2, -P (R cc) 3 + X -, -P (OR cc) 2, -P (OR cc) _{^{3 + X -, -P (=}} O) (R aa) 2, includes a ^{-P (= O) (oR cc} ) 2, and ^{-P (= O) (N (} R bb) 2) 2, where , X ⁻ , R ^aa , R ^bb , and R ^cc are as defined herein. Oxygen protecting groups are well known in the art, Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, in John Wiley & Sons, 1999 (herein incorporated by reference), described in detail Including what is done.

Illustrated oxygen protective groups are not limited to these, but are limited to methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), benzyloxymethyl (BOM). , P-Methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), guaiacol methyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siroxymethyl, 2-methoxy Ethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, Tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1-[(2-chloro-4) -Methyl) phenyl] -4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a, 4,5,6,7 , 7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1- Methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl , P-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2, 6-Dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picoryl, 4-picoryl, 3-methyl-2-picoryl N-oxide, diphenylmethyl, p, p'-dinitrobenzhydryl, 5-dibenzo Suberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4'-bromophenacyl) Oxyphenyl) diphenylmethyl, 4,4', 4 "-tris (4,5-dichlorophthalimidephenyl) methyl, 4,4', 4"-tris (levlinoyloxyphenyl) methyl, 4,4', 4 "-Tris (benzoyloxyphenyl) methyl, 3- (imidazole-1-yl) bis (4', 4" -dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-pyrenylmethyl, 9 -Anthryl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S, S-dioxide, trimethylsilyl (TMS) , Triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyltexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) , Tribenzylsilyl, tri-p-kisilylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formalt, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacet Tart, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylene) Dithio) Pentanoart (Rebrinoyl dithioacetal), Pivaloart, Adamant Art, Crotonato, 4-methoxycrotonato, Benzoyl, p-phenylbenzoart, 2,4,6-trimethylbenzoart (Mesitoart), Methylcarbo Nate, 9-fluorenylmethylcarbonate (Fmoc), ethylcarbonate, 2,2,2-trichloroethylcarbonate (Troc), 2- (trimethylsilyl) ethylcarbonate (TMSEC), 2- (phenylsulfonyl) Ethylcarbonate (Psec), 2- (triphenylphosphonio) ethylcarbonate (Peoc), isobutylcarbonate, vinylcarbonate, allylcarbonate, t-butylcarbonate (BOC or Boc), p-nitrophenylcarbo Nart, benzyl carbonate, p-methyl Sibenzylcarbonate, 3,4-dimethoxybenzylcarbonate, o-nitrobenzylcarbonate, p-nitrobenzylcarbonate, S-benzylthiocarbonate, 4-ethoxy-1-naphthylcarbonate, methyldithiocarbonate, 2-Iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl, 4- (methylthiomethoxy) ) Butyrate, 2- (methylthiomethoxymethyl) benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate , 2,4-Bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butanoate, o- (methoxyacyl) benzoart , Α-Naftate, Nitrat, Alkyl N, N, N', N'-Tetramethylphosphologiamidate, Alkyl N-phenylcarbamate, Borate, Dimethylphosphinochi oil, Alkyl 2,4-dinitrophenylsulfenate , Sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In some embodiments, the oxygen protecting group is silyl. In some embodiments, the oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl ( TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allylcarbonate, 2,2,2-trichloroethylcarbonate (Troc), 2-trimethylsilylethylcarbonate, methoxymethyl (MOM) ), 1-ethoxyethyl (EE), 2-methoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthio Methyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxy It is benzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

In some embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protective groups are not limited to these, but are limited to -R ^aa , -N (R ^bb ) ₂ , -C (= O) SR ^aa , -C (= O) R ^aa , -CO ₂ R ^aa , -C ( = O) N (R ^bb ) ₂ , -C (= NR ^bb ) R ^aa , -C (= NR ^bb ) OR ^aa , -C (= NR ^bb ) N (R ^bb ) ₂ , -S (= O) _{^{R aa, -SO 2 R aa,}} -Si (R aa) 3, -P (R cc) 2, -P (R cc) 3 + X -, -P (OR cc) 2, -P (OR cc) _{^{3 + X -, -P (=}} O) (R aa) 2, includes a ^{-P (= O) (oR cc} ) 2, and ^{-P (= O) (N (} R bb) 2) 2, where R ^aa , R ^bb , and R ^cc are as defined herein. Sulfur protecting groups are well known in the art, Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd edition, in John Wiley & Sons, 1999 (herein incorporated by reference), described in detail Including what is done. In some embodiments, the sulfur protecting group is acetamide methyl, t-Bu, 3-nitro-2-pyridinesulphenyl, 2-pyridine-sulphenyl, or triphenylmethyl.

A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group in order to maintain electrical neutrality. The anionic counterion may be monovalent (ie, contains one formal negative charge). The anionic counterion may be multivalent, such as divalent or trivalent (ie, contains more than one formal negative charge). Illustrated counterions are halide ions (eg, F ⁻ , Cl ⁻ , Br ⁻ , I ⁻ ), NO ₃ ⁻ , ClO ₄ ⁻ , OH ⁻ , H ₂ PO ₄ ⁻ , HCO ₃ ⁻ _, HSO ₄ ^−. , Sulfonate ions (eg, methanesulphonate, trifluoromethanesulphonate, p-toluenesulphonate, benzenesulphonate, 10-campar sulphonate, naphthalene-2-sulphonate, naphthalene-1-sulfonic acid-5-sulphonates, ethane-1-sulfonic acid-2-sulfonate and the like), carboxylate ions (as an example, acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, _{^{etc.), BF 4 -, PF 4}} -, PF 6 _{^{-, AsF 6 -, SbF 6}} -, B [3,5- (CF 3) 2 C 6 H 3] 4] -, B (C 6 F 5) 4 -, BPh 4 -, Al (OC (CF 3 ) ₃ ) ₄ ⁻ , and carbolan anion (eg, CB ₁₁ H ₁₂ ⁻ or (HCB ₁₁ Me ₅ Br ₆ ) ⁻ ). Examples of counterions that may be multivalent are CO ₃ ^2- , HPO ₄ ^2- , PO ₄ ^3- _, B ₄ O ₇ ^2- , SO ₄ ^2- , S ₂ O ₃ ^2- , carboxylate anion. (For example, tartrate, citrat, fumarat, maleart, malat, malonate, gluconate, succinate, glutarate, adipert, pimerato, sverato, azelato, sebacart, salicylate, phthalate, aspartate, glutamate, etc.), and carborane.

As used herein, the use of the phrase "at least one presence" refers to the presence of 1, 2, 3, 4, or more, but in a range, eg, 1-4, 1-3, The presence of 1-2, 2-4, 2-3, or 3-4 is also comprehensively included.

Other Definitions As used herein, the term "salt" means any and all salts and includes pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is within the range of appropriate medical judgment and is used in contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc. Means salt that is suitable for and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berger et al. Describe in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, etc., or with organic acids such as acetic acid, oxalic acid. , Maleic acid, tartrate acid, citric acid, succinic acid, malonic acid and the like, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, hydrogen sulfate, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, citric acid, cyclopentane. Propionic acid, digluconic acid, dodecyl sulfate, ethanesulfonic acid, formic acid, fumaric acid, glucoheptonic acid, glycerophosphate, gluconic acid, hemisulfate, heptanic acid, hexanoic acid, hydroiodic acid, 2-hydroxy-ethanesulfonate, lactobionic acid , Lactic acid, lauric acid, lauryl sulfate, malic acid, maleic acid, malonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitrate, oleic acid, oxalic acid, palmitic acid, pamoic acid, pectinic acid, persulfate , 3-Phenylpropionic acid, phosphoric acid, picric acid, pivalic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyan acid, p-toluenesulfonic acid, undecanoic acid, salts of valeric acid and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ^ammonium, N _{+ (C 1 to 4 alkyl) 4} ^- include salts of. Typical alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, where appropriate, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonic acids, and aryl sulfonic acids. And the like, non-toxic ammonium formed using, quaternary ammonium, and amine cations are included. The compounds provided herein are also provided as free bases and can be administered.

It should also be understood that compounds that have the same molecular formula but differ in the bonding properties or arrangement of the atoms, or the arrangement of the atoms in space, are also called "isomers". Isomers with different atomic arrangements in space are called "stereoisomers".

The terms "composition" and "formulation" are used interchangeably.

The "subject" intended for administration is a human (ie, male or female of any age group, eg, a pediatric subject (eg, infant, child, or adolescent), or an adult subject (eg, young adult, middle-aged). It means an adult or an elderly adult)), or a non-human animal. In certain embodiments, the non-human animal is a mammal (eg, a primate (eg, cynomolgus monkey or lizard monkey), a commercially related mammal (eg, cow, pig, horse, sheep, goat, cat, or). Dogs), or birds (eg, commercially related birds such as chickens, ducks, geese, or primates). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. Non-human animals can be male or female at any stage of development. The non-human animal may be a transgenic animal or a genetically engineered animal. The term "patient" means a human subject in need of treatment for a disease.

The terms "administer," "administer," or "administer" are used to implant, absorb, orally ingest, inject, inhale, or inhale a compound or composition thereof described herein in or on a subject. It means to introduce it separately.

The terms "treat," "treat," and "treat" mean to ameliorate, alleviate, delay the onset, or impede the progression of the diseases described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have occurred or have been observed. In other embodiments, the treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment can be administered to susceptible subjects before the onset of symptoms. Treatment may be continued after symptoms have resolved, for example to delay or prevent recurrence.

The "effective amount" of a compound described herein means an amount sufficient to elicit the desired biological response. Effective amounts of the compounds described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the conditions being treated, the mode of administration, the age and health of the subject, and the like. is there. In certain embodiments, the effective amount is a therapeutically effective amount. Alternatively, in a separate method or use, the invention may be used as a prophylactic treatment if noted and effective. In certain embodiments, the effective amount is the amount of compound described herein in a single dose. In certain embodiments, the effective amount is a combination of the compounds described herein in multiple doses.

A "therapeutically effective amount" of a compound described herein is sufficient to provide a therapeutic benefit in the treatment of the condition or to delay or minimize one or more symptoms associated with the condition. The amount. A therapeutically effective amount of a compound means the amount of therapeutic agent alone or in combination with other therapies that provides therapeutic benefits in the treatment of the condition. The term "therapeutically effective amount" may include an amount that improves the overall therapy, reduces or avoids the symptoms, signs, or causes of the condition and / or enhances the therapeutic efficacy of another therapeutic agent. it can. In certain embodiments, the therapeutically effective amount is sufficient to treat any of the described diseases or conditions.

As used herein, "inhibiting", "inhibiting", "inhibiting", and "inhibiting" etc. reduce, slow down, stop, or prevent the activity of biological processes (eg, tumor growth). Means the ability of a compound. In certain embodiments, the inhibition is about 45% -50%. In certain embodiments, the inhibition is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99.9%, or 100%.

Detailed Description of Some Embodiments The present invention will be described in detail below with reference to embodiments and the like of the present invention. The present invention relates to compounds (eg, compounds represented by formulas (I), (II), (III), and (IV)), and pharmaceutically acceptable salts or isotope-labeled derivatives thereof. The pharmaceutical composition is provided. The present invention is a method of treating a proliferative disorder in a subject (eg, inhibiting tumor growth and / or treating cancer) in an effective amount of a compound or compound provided herein. Methods are also provided that include administering the composition. The compounds or compositions may be administered as monotherapy or in combination with other therapies, as described herein. In yet another aspect, the invention provides a method of synthesizing compounds of formulas (I), (II), (III), and (IV), and synthetic intermediates useful for this purpose.

式中：
Ｒ^Ｎ１およびＲ^Ｎ２は、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または窒素保護基であるか、任意に、Ｒ^Ｎ１およびＲ^Ｎ２は、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルまたは任意に置換されていてもよいヘテロアリールを形成し；
Ｒ^Ｐ１は、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｘは、水素または−ＯＲ^Ｘａであり；
Ｒ^Ｙは、水素または−ＯＲ^Ｙａであり；
Ｒ^ＸａおよびＲ^Ｙａは、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であるか、任意に、Ｒ^ＸａおよびＲ^Ｙａは、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルを形成し；および
ｎは、１または２である、
で表される化合物およびその薬学的に許容し得る塩および同位体標識された誘導体を提供する。 In one aspect, the present invention relates to formula (I) :.

During the ceremony:
^RN1 and ^RN2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or nitrogen protecting group, or optionally ^RN1 and ^RN2. , Linked together with intervening atoms to form optionally substituted heterocyclyls or optionally substituted heteroaryls;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, or optionally R ^Xa and R ^Ya. , Linked together with intervening atoms to form a heterocyclyl that may be optionally substituted; and n is 1 or 2.
Provided are a compound represented by the above and a pharmaceutically acceptable salt and isotope-labeled derivative thereof.

またはその薬学的に許容し得る塩または同位体標識された誘導体である。ある態様において、式（Ｉ）で表される化合物は、化合物（１）、またはその薬学的に許容し得る塩または同位体標識された誘導体ではない。ある態様において、化合物（１）およびそのすべての薬学的に許容し得る塩および同位体標識された誘導体は、本発明から除外される。 In some embodiments, the compound of formula (I) is compound (1):

Or its pharmaceutically acceptable salt or isotope-labeled derivative. In some embodiments, the compound of formula (I) is not compound (1), or a pharmaceutically acceptable salt or isotope-labeled derivative thereof. In some embodiments, compound (1) and all pharmaceutically acceptable salts and isotope-labeled derivatives thereof are excluded from the present invention.

の１つまたはその薬学的に許容し得る塩または同位体標識された誘導体である。 In some embodiments, the compound of formula (I) has the following formula:

One or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

の１つまたはその薬学的に許容し得る塩または同位体標識された誘導体である。 In some embodiments, the compound of formula (I) has the following formula:

One or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

およびその同位体標識された誘導体および薬学的に許容し得る塩からなる群から選択される。 In some embodiments, the compound of formula (I) is

And its isotope-labeled derivatives and pharmaceutically acceptable salts.

式中：
Ｒ^Ｎ１およびＲ^Ｎ２は、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または窒素保護基であるか、任意に、Ｒ^Ｎ１およびＲ^Ｎ２は、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルまたは任意に置換されていてもよいヘテロアリールを形成し；
Ｒ^Ｐ１およびＲ^Ｐ２は、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｘは、水素または−ＯＲ^Ｘａであり；
Ｒ^Ｙは、水素または−ＯＲ^Ｙａであり；
Ｒ^ＸａおよびＲ^Ｙａは、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であるか、任意に、Ｒ^ＸａおよびＲ^Ｙａは、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルを形成し；および
ｍは、０または１である、
で表される化合物およびその薬学的に許容し得る塩および同位体標識された誘導体を提供する。 In another aspect, the present invention relates to formula (II) :.

During the ceremony:
^RN1 and ^RN2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or nitrogen protecting group, or optionally ^RN1 and ^RN2. , Linked together with intervening atoms to form optionally substituted heterocyclyls or optionally substituted heteroaryls;
^RP1 and ^RP2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, or optionally R ^Xa and R ^Ya. , Linked together with intervening atoms to form a heterocyclyl that may be optionally substituted; and m is 0 or 1.
Provided are a compound represented by the above and a pharmaceutically acceptable salt and isotope-labeled derivative thereof.

の１つまたはその薬学的に許容し得る塩または同位体標識された誘導体である。 In some embodiments, the compound of formula (II) has the following formula:

One or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

；
の１つまたはその薬学的に許容し得る塩または同位体標識された誘導体である。 In some embodiments, the compound of formula (II) has the following formula:

;
One or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

およびその薬学的に許容し得る塩および同位体標識された誘導体からなる群から選択される。 In some embodiments, the compound of formula (II) is

And its pharmaceutically acceptable salts and isotope-labeled derivatives are selected from the group.

式中：
Ｒ^Ｏは、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｐ１は、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｘは、水素または−ＯＲ^Ｘａであり；
Ｒ^Ｙは、水素または−ＯＲ^Ｙａであり；
Ｒ^ＸａおよびＲ^Ｙａは、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であるか、任意に、Ｒ^ＸａおよびＲ^Ｙａは、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルを形成し；および
ｎは、１または２である、
で表される化合物およびその薬学的に許容し得る塩および同位体標識された誘導体を提供する。 In another aspect, the present invention relates to formula (III):

During the ceremony:
^RO is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, or optionally R ^Xa and R ^Ya. , Linked together with intervening atoms to form a heterocyclyl that may be optionally substituted; and n is 1 or 2.
Provided are a compound represented by the above and a pharmaceutically acceptable salt and isotope-labeled derivative thereof.

またはその薬学的に許容し得る塩である。ある態様において、式（ＩＩＩ）で表される化合物は、（Ｄ−６）、またはその薬学的に許容し得る塩または同位体標識された誘導体ではない。ある態様において（Ｄ−６）、およびそのすべての薬学的に許容し得る塩および同位体標識された誘導体は、本発明から除外される。 In some embodiments, the compound of formula (III) is:

Or its pharmaceutically acceptable salt. In some embodiments, the compound of formula (III) is not (D-6), or a pharmaceutically acceptable salt or isotope-labeled derivative thereof. In certain embodiments (D-6), and all pharmaceutically acceptable salts and isotope-labeled derivatives thereof, are excluded from the present invention.

の１つまたはその薬学的に許容し得る塩または同位体標識された誘導体である。 In some embodiments, the compound of formula (III) has the following formula:

One or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

の１つまたはその薬学的に許容し得る塩または同位体標識された誘導体である。 In some embodiments, the compound of formula (III) has the following formula:

One or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

およびその薬学的に許容し得る塩および同位体標識された誘導体からなる群から選択される。 In some embodiments, the compound of formula (III) is

And its pharmaceutically acceptable salts and isotope-labeled derivatives are selected from the group.

式中：
Ｒ^Ｏは、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｐ１は、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であり；
Ｒ^Ｘは、水素または−ＯＲ^Ｘａであり；
Ｒ^Ｙは、水素または−ＯＲ^Ｙａであり；
Ｒ^ＸａおよびＲ^Ｙａは、独立して、水素、任意に置換されていてもよいアルキル、任意に置換されていてもよいアシル、または酸素保護基であるか、任意に、Ｒ^ＸａおよびＲ^Ｙａは、介在原子と一緒に連結して、任意に置換されていてもよいヘテロシクリルを形成し；および
ｍは、０または１である、
で表される化合物および薬学的に許容し得る塩および同位体標識された誘導体を提供する。 In yet another aspect, the present invention describes formula (IV):

During the ceremony:
^RO is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, or optionally R ^Xa and R ^Ya. , Linked together with intervening atoms to form a heterocyclyl that may be optionally substituted; and m is 0 or 1.
Provided are compounds represented by and pharmaceutically acceptable salts and isotope-labeled derivatives.

の１つまたはその薬学的に許容し得る塩または同位体標識された誘導体である。 In some embodiments, the compound of formula (IV) has the following formula:

One or a pharmaceutically acceptable salt or isotope-labeled derivative thereof.

およびその薬学的に許容し得る塩および同位体標識された誘導体からなる群から選択される。 In some embodiments, the compound of formula (IV) is

And its pharmaceutically acceptable salts and isotope-labeled derivatives are selected from the group.

The compounds provided herein may be in the form of hydrates, solvates or polymorphs in optionally pharmaceutically acceptable carriers or excipients. The present invention also provides a stereoisomer of any one of the compounds provided herein. The compounds provided herein may exist as polymorphs, and the compounds of the invention may be either a single crystalline form or a mixture of two or more crystalline forms. Good. The compounds provided herein can be present in amorphous form or can be solvates such as anhydrides or hydrates.

The present invention includes isotope-labeled derivatives of the compounds provided herein and pharmaceutically acceptable salts thereof. Isotope-labeled compounds are those provided herein except that one or more of the atoms are replaced by an atom having an atomic mass or mass number that is different from the atomic mass or mass number commonly found in nature. Equivalent. Examples of isotopes that can be incorporated into compounds of the present invention, hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, bromine, and chlorine, such ^{as, 2 H, 3 H, 11} C, 13 Includes C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²³ I, and ¹²⁵ I and the like.

Isotopically labeled compounds, for example, ^{3 H} and / or ^{14 C} compounds radioactive isotopes incorporated such are useful in pharmaceutical and / or substrate tissue distribution assays. Isotopes ³ H and ¹⁴ C are considered useful because they can be easily prepared and detected. Isotopes ¹¹ C and ¹⁸ F are useful in PET (positron emission tomography). Isotope ¹²⁵ I is considered useful in SPECT (single photon emission computed tomography) and may be useful in brain imaging. Substitution with heavier isotopes such as ^{2 H} may cause certain therapeutic advantages such as reducing the increase or dosage requirements vivo half-life greater metabolic stability, therefore, under certain circumstances It is considered useful. Isotopic-labeled compounds can be uniformly prepared by using readily available isotope-labeling reagents in place of non-isotope-labeled reagents and following the procedures disclosed in the scheme and / or examples below. it can.

The compounds provided herein can be used as chemical probes to capture the target proteins of biologically active low molecular weight compounds. Specifically, the compound of the present invention has J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5, 2003, p. 492-498 or It can be converted into an affinity chromatography probe, a photoaffinity probe, or the like by introducing a labeling group, a linker, or the like by the method described in WO 2007/139149 or the like.

Examples of labeling groups, linkers and the like used in such chemical probes include groups belonging to the following groups (1) to (5). (1) Photoaffinity labeling group (for example, benzoyl group, benzophenone group, azido group, carbonyl azide group, diaziridine group, enone group, diazo group, nitro group, etc.) and chemical affinity group (for example, alpha carbon atom is halogen Protein-labeling groups such as atomically substituted ketone groups, carbamoyl groups, ester groups, alkylthio groups, α, β-unsaturated ketones, Michael acceptors such as esters, oxylan groups, etc., (2) -SS- , -O-Si-O-, cleaving linkers such as monosaccharides (glucose group, galactose group, etc.), disaccharides (lactose, etc.), and oligopeptide linkers that can be cleaved by enzymatic reaction, (3) biotin, 3 -Fishing tag groups such as propionyl group (44-difluoro-5,7-dimethyl-4H-3a, 4a-diaza-4-bora-s-indacene-3-yl), (4) ¹²⁵ I, ³² P, ³ Radiolabeling groups such as H, ^14C ; fluorescein, rhodamine, dancil, umveriferone, 7-nitroflazanyl, 3- (4,4-difluoro-5,7-dimethyl-4H-3a, 4a-diaza-4-bora) -S-Indacene-3-yl) Fluorescent labeling group such as propionyl group; Chemically emitting group such as luciferin and luminol; Marker capable of detecting heavy metal ion such as lanthanoid metal ion and radium ion, and (5) glass beads , Glass bed, microtiter plate, agarose beads, agarose bed, polystyrene beads, polystyrene bed, nylon beads, nylon bed and other groups to be bonded to a solid phase carrier.

A probe prepared by introducing a labeling group or the like selected from the above groups (1) to (5) into the compound of the present invention according to the method or the like described in any of the above documents is a new drug discovery target. It can be used as a chemical probe for identifying marker proteins useful for searching.

Examples of "salts" as used herein include salts with inorganic acids, salts with organic acids, salts with acidic amino acids, and pharmaceutically acceptable salts are particularly preferred. In addition, the salt of the compound of the present invention includes an anhydride of the pharmaceutically acceptable salt thereof and a solvate of the pharmaceutically acceptable salt such as hydrate. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid and the like, and preferred examples of salts with organic acids include acetic acid and succinic acid. , Fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferred examples of the salt with an acidic amino acid include a salt with aspartic acid, glutamic acid and the like.

When the compound according to the present invention is obtained as a salt of the compound or a hydrate of the compound, the salt and the hydrate can be converted into a free form of the compound by a conventional method.

Group ^{R N1, R N2, R O} , R P1, R P2, R X, R Y, n, and m
All definitions provided below apply to all compounds represented by the formulas (I), (II), (II), and (IV) described herein.

で表される。ある態様において、Ｒ^Ｎ２は、水素である。ある態様において、Ｒ^Ｎ２は、任意に置換されていてもよいアルキルである。ある態様において、Ｒ^Ｎ２は、任意に置換されていてもよいアシルである。ある態様において、Ｒ^Ｎ２は、窒素保護基である。ある態様において、Ｒ^Ｎ２は、エステル保護基である。ある態様において、Ｒ^Ｎ２は、アロック保護基である。 As generally defined herein, are ^RN1 and ^RN2 independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or nitrogen protecting group? , Optionally, ^RN1 and ^RN2 are linked together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. In some embodiments, ^RN1 is hydrogen. In some embodiments, ^RN1 is an optionally substituted alkyl. In some embodiments, ^RN1 is an optionally substituted acyl. In some embodiments, ^RN1 is a nitrogen protecting group. In some embodiments, ^RN1 is an ester protecting group. In some ^{embodiments, R N1} is an alloc protecting group. "Alock" is the following formula:

It is represented by. In some embodiments, ^RN2 is hydrogen. In some embodiments, ^RN2 is an optionally substituted alkyl. In some embodiments, ^RN2 is an optionally substituted acyl. In some embodiments, ^RN2 is a nitrogen protecting group. In some embodiments, ^RN2 is an ester protecting group. In some ^{embodiments, R N2} is alloc protecting group.

In some embodiments ^{, both RN1} and ^RN2 are hydrogen. In some embodiments, ^RN1 is hydrogen; and ^RN2 is a nitrogen protecting group. In some embodiments, ^RN1 is hydrogen; and ^RN2 is alok. In some embodiments, ^RN1 and ^RN2 are linked together with intervening atoms to form a heterocyclyl that may be optionally substituted. In some embodiments, ^RN1 and ^RN2 are linked together with intervening atoms to form heteroaryls that may be optionally substituted.

As commonly defined herein, ^RP1 is a hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group. In some embodiments, ^RP1 is hydrogen. In some embodiments, ^RP1 is an optionally substituted alkyl. In some embodiments, ^RP1 is an optionally substituted acyl. In some embodiments, ^RP1 is an oxygen protecting group. In some embodiments, ^RP1 is silyl (eg, trialkylsilyl). In some embodiments, ^RP1 is tert-butyldimethylsilyl (TBS or TBDMS).

As commonly defined herein, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

As commonly defined herein, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

Generally as defined herein, ^{R X} is hydrogen or ^{-OR Xa.} In some embodiments, ^RX is hydrogen. In some ^embodiments, a R X ^{-OR Xa.} In some embodiments, ^{R X} is -OH.

As commonly defined herein, ^RXa is a hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group. In some embodiments, ^RXa is hydrogen. In some embodiments, ^RXa is an optionally substituted alkyl. In some embodiments, ^RXa is an optionally substituted acyl. In some embodiments, ^RXa is an oxygen protecting group.

As commonly defined herein, ^RY is hydrogen or -OR ^Ya . In some embodiments, ^RY is hydrogen. In some embodiments, ^RY is −OR ^Ya . In some embodiments, ^RY is −OH.

As commonly defined herein, R ^Ya is a hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group. In some embodiments, R ^Ya is hydrogen. In some embodiments, R ^Ya is an optionally substituted alkyl. In some embodiments, R ^Ya is an optionally substituted acyl. In some embodiments, R ^Ya is an oxygen protecting group.

In some embodiments, ^RXa and R ^Ya are linked together with an intervening atom to form an optionally substituted heterocyclyl (eg, a optionally substituted 5-membered heterocyclyl).

In some embodiments, ^RX and ^RY are hydrogen. In some ^{embodiments, R} X is an ^{-OR Xa;} and ^R Y are ^{-OR Ya.} In some embodiments, ^{R X} and ^{R Y} are -OH. In some embodiments, ^RX is hydrogen; and ^RY is -OR ^Ya . In some embodiments, ^RX is hydrogen; and ^RY is -OH.

As commonly defined herein, ^RP2 is a hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group. In some embodiments, ^RP2 is hydrogen. In some embodiments, ^RP2 is an optionally substituted alkyl. In some embodiments, ^RP2 is an optionally substituted acyl. In some embodiments, ^RP2 is an oxygen protecting group. In some embodiments, ^RP2 is silyl (eg, trialkylsilyl). In some embodiments, ^RP2 is tert-butyldimethylsilyl (TBS or TBDMS).

As commonly defined herein, ^RO is a hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group. In some embodiments, the ^RO is an optionally substituted alkyl. In some embodiments, the ^RO _{is a C 1-6} alkyl which may be optionally substituted. In some embodiments, the ^RO is an unsubstituted C _1-6 alkyl. In some embodiments, the ^RO _{is a C 1-3} alkyl which may be optionally substituted. In some embodiments, the ^RO is an unsubstituted C _1-3 alkyl. In some embodiments, the ^RO is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. In some embodiments, the ^RO is methyl. In some embodiments, the ^RO is an optionally substituted acyl. In some embodiments, the ^RO is an oxygen protecting group.

Pharmaceutical Compositions, Kits, and Administrations The present invention is labeled with a compound of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or isotope thereof. Provided are pharmaceutical compositions containing derivatives and pharmaceutically acceptable excipients. In certain embodiments, the compounds described herein, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, are provided in pharmaceutical compositions in effective amounts (eg, therapeutically effective amounts). To.

The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparation methods include the compounds provided herein (ie, the "active ingredient") with a carrier or excipient and / or one or more other sub-ingredients, followed by If necessary and / or desired, the product comprises molding and / or packaging into the desired single or multiple dose unit.

The pharmaceutical composition of the present invention can be prepared by a known method such as the method described in the general rules for the preparation of the Japanese Pharmacopoeia, 16th edition, the United States Pharmacopeia, and the European Pharmacopoeia, 9th edition. The pharmaceutical composition of the present invention can be appropriately administered to a patient according to the dosage form.

The pharmaceutical composition can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as multiple single unit doses. A "unit dose" is an individual amount of a pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient administered to the subject and / or a favorable fraction of such dose, such as one-half or one-third of such dose. Is.

Relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any additional ingredients in the pharmaceutical compositions described herein are individual differences, sizes, and / or conditions of the subject being treated. And moreover, it will vary depending on the route by which the composition is administered. The composition may contain an active ingredient between 0.1% and 100% (w / w).

Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersants and / or granulants, surfactants and / or emulsifiers, disintegrants. Includes binders, preservatives, buffers, lubricants, and / or oils. Excipients such as cocoa butter and suppository waxes, colorants, dressings, sweeteners, flavors, fragrances may also be present in the composition.

The compounds provided herein are typically formulated in unit dosage forms for ease of administration, dosage uniformity. However, it will be appreciated that the total daily use of the compositions described herein will be determined by the physician within the scope of appropriate medical judgment. The specific therapeutically effective dose level of any particular subject or organism is the disease being treated, and the severity of the disorder; the activity of the specific active ingredient used; the specific composition used; Subject's age, weight, overall health, gender, diet; time of administration, route of administration, excretion rate of specific active ingredient used; duration of treatment; in combination with specific active ingredient used , Or drugs used at the same time; and will depend on a variety of factors, including similar factors well known in medicine.

The compounds of the invention and the compositions provided herein are transintestinal (eg, oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, trans. By any route, including skin, intradermal, rectal, intravaginal, intraperitoneal, localized (such as powders, ointments, creams, and / or infusions), mucosa, nasal, buccal, sublingual It can be administered by intratracheal infusion, bronchial infusion, and / or inhalation; and / or as an oral ointment, nasal ointment, and / or aerosol. Specifically intended routes are oral administration, intravenous administration (eg, systemic intravenous infusion), topical administration via blood and / or lymphatic supply, and / or direct administration to the affected area. In general, the most appropriate route of administration includes the nature of the agent (eg, its stability in the gastrointestinal environment) and / or the condition of the subject (eg, whether the subject can tolerate oral administration). It depends on various factors.

The exact amount of a compound provided herein that is required to achieve an effective amount is, for example, the species, age, and general conditions of interest, the severity of side effects or disorders, and the identity of a particular compound. , It will vary depending on the subject depending on the administration mode and the like. Effective amounts may be included in single doses (eg, single oral doses) or multiple doses (eg, multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses are different or substantially the same amount herein. Includes the compounds described in the book. In certain embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the frequency of administering multiple doses to the subject or multiple doses to tissues or cells is non-existent. In limited cases, a dose of 3 times a day, a dose of 2 times a day, a dose of once a day, a dose of once every 1 day, a dose of once every 3 days, a dose of once a week, 2 It can be a weekly dose, a three-week dose, or a four-week dose, or even slower dose-controlled delivery over a selected period of time using a drug delivery device. In certain embodiments, the frequency with which a subject is administered multiple doses or is applied to a tissue or cell is a single dose per day. In certain embodiments, the frequency with which a subject is administered multiple doses or is applied to a tissue or cell in multiple doses is a dose twice daily. In certain embodiments, the frequency with which the subject is administered multiple doses or the tissue or cell is administered multiple doses is a dose of 3 times per day. In certain embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the duration between the first and last doses of the multiple doses is about or at least one day. 2, 2 days, 4 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 Year, 10 years, 15 years, 20 years, or lifespan of a subject, tissue, or cell. In certain embodiments, the duration between the first and last doses of multiple doses is about or at least 3 months, 6 months, or 1 year. In certain embodiments, the duration between the first and last doses of multiple doses is the lifespan of the subject, tissue, or cell. In certain embodiments, the doses described herein (eg, single dose, or any dose of multiple doses) are independently between 0.001 mg / kg and 0.01 mg / kg. , 0.01 mg / kg to 0.1 mg / kg, 0.1 mg / kg to 1 mg / kg (including both ends) provided herein. Examples are at least about 0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 5 in the dosage form. , 20, 25, or 50 mg of active compound, or a dosage form thereof.

In some embodiments, the doses described herein (eg, single doses, or any multiple doses) are independently described herein in an ^{amount of 1.0 μg / m 2 to} 1.0 mg / m ^2. Comprehensively comprising the provided compounds (eg, compound (1) or a pharmaceutically acceptable salt thereof). In some embodiments, the doses described herein (eg, single dose, or any dose of multiple doses) are independently 1.0 μg / m ^{2 to} 100.0 μg / m ² , 1.0 μg. ^{/ m 2 ~50μg / m 2,} 10μg / m 2 ~50μg / m 2 or 10μg ^{/ m} 2 ~30μg ^/ m compounds provided herein of ^2, as (e.g., compound (1) or a pharmaceutically Comprehensively contains acceptable salts). Examples are approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, A dosage form having 33, 34, 35, 36, 37, 38, 39, and 40 μg of the compounds provided herein (eg, compound (1) or a pharmaceutically acceptable salt thereof).

In some embodiments, the compounds provided herein (eg, compound (1) or a pharmaceutically acceptable salt thereof) are approximately 1, 2, 3, 4, 5, 6, 7, 8, 9. Dosed once every 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or every 30 days. .. In some embodiments, the compounds provided herein (eg, compound (1) or a pharmaceutically acceptable salt thereof) are administered approximately twice a month. In some embodiments, the compounds provided herein (eg, compound (1) or a pharmaceutically acceptable salt thereof) are administered once approximately every 15 days for the duration of treatment. In some embodiments, the compounds provided herein (eg, compound (1) or a pharmaceutically acceptable salt thereof) are administered on days 1 and 15 of the 28-day cycle. In some embodiments, the compound provided herein (eg, compound (1) or a pharmaceutically acceptable salt thereof) is approximately 25 μg / m on days 1 and 15 of the approximately 28-day cycle. Medicated in ^2. In some embodiments, the compounds provided herein (eg, compound (1) or a pharmaceutically acceptable salt thereof) are at 25 μg / m ^{2 on} days 1 and 15 of the 28-day cycle. Be dosed. The number of cycles is determined by the doctor.

The dose ranges described herein provide guidance for administering the provided pharmaceutical composition to an adult. For example, the amount administered to a child or adolescent can be determined by a doctor or one of ordinary skill in the art and can be lower or the same as the amount administered to an adult.

Kits (eg, pharmaceutical packs) are also included by this disclosure. The kit provided may include the pharmaceutical composition or the compounds and containers provided herein (eg, vials, ampoules, bottles, syringes, and / or removal containers, or other suitable containers). In some embodiments, the kit provided may further comprise a second container containing a pharmaceutical composition or a pharmaceutical excipient for diluting or suspending the compounds provided herein. In some embodiments, the pharmaceutical compositions or compounds provided in the first and second containers are combined to form a unit dosage form. The kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions.

Methods and Uses of Treatment As shown herein, the compounds represented by formulas (I), (II), (III), and (IV) have significant tumor vascular remodeling effects and anti-CAF activity. , Therefore it has potential for the treatment of cancer and / or inhibition of tumor growth.

A method of treating a proliferative disorder in a subject, which comprises administering to the subject an effective amount of compound (1), or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a pharmaceutical composition thereof. Including, methods are provided herein. The present invention also includes compounds provided herein for use in treating proliferative disorders in a subject, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof. provide. The present invention also uses the compounds provided herein, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof for the manufacture of a medicament for treating a proliferative disorder. provide. Examples of proliferative disorders are described herein.

Provided herein is the administration of an effective amount of a compound provided herein, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a pharmaceutical composition thereof to a subject. Is a method of treating cancer in a subject, including. The present invention also provides the compounds provided herein, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof for use in the treatment of cancer in a subject. To do. The present invention is also the compound provided herein, or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a medicament thereof, for the manufacture of a medicament for treating cancer. The composition is provided.

A method of inhibiting tumor growth in a subject, which comprises administering to the subject a compound (1), or a pharmaceutically acceptable salt or isotope-labeled derivative thereof, or a pharmaceutical composition thereof. Provided herein. Also provided herein are compounds provided herein for use in inhibiting tumor growth in a subject, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof. Has been done. The present invention also provides the use of the compounds provided herein, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof for producing a medicament for inhibiting tumor growth. To do.

"Proliferative disease" refers to a disease caused by abnormal growth or expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders include 1) pathogenic proliferation of normally dormant cells; 2) pathological migration of cells from their normal location (eg, metastasis of neoplastic cells); 3) matrix metalloproteinases. Pathogenic expression of proteolytic enzymes such as (eg, collagenase, zelatinase, and elastase); or 4) may be associated with pathological angiogenesis such as proliferative retinopathy and tumor metastasis. Illustrated proliferative disorders include cancer (ie, "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory disorders, and autoimmune disorders.

The term "angiogenesis" refers to the physiological process by which new blood vessels are formed from existing blood vessels. Angiogenesis differs from angiogenesis, which is de novo formation from mesoderm cell precursors of endothelial cells. The first blood vessels of the developing embryo are formed through angiogenesis, after which angiogenesis is responsible for most angiogenesis during normal or abnormal development. Angiogenesis is an essential process in growth and development, as well as wound healing and granulation tissue formation. However, angiogenesis is also a fundamental step in the transition of tumors from benign to malignant states, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis can be chemically stimulated by angiogenic proteins such as growth factors (eg, VEGF). "Pathological angiogenesis" refers to abnormal (eg, excess or inadequate) angiogenesis that corresponds to and / or is associated with the disease.

The terms "neoplasm" and "tumor" are used interchangeably herein to mean an abnormal mass of tissue in which the growth of the mass surpasses and does not coordinate with the growth of normal tissue. .. The neoplasm or tumor can be "benign" or "malignant" depending on the following characteristics: degree of cell differentiation (including morphology and functionality), rate of growth, local infiltration, metastasis. "Benign neoplasms" are generally well-differentiated, characteristically slower to grow than malignant neoplasms, and remain localized at the primary site. In addition, benign neoplasms do not have the ability to infiltrate, invade, or metastasize to distal sites. Illustrated benign neoplasms include, but are not limited to, lipomas, chondromas, adenomas, acrocordons, senile hemangiomas, seborrheic keratosis, moles, and sebaceous hyperplasia. In some cases, some "benign" tumors can later develop malignant neoplasms, which can result from additional genetic alterations in the neoplastic cell subpopulation of the tumor. Tumors are referred to as "premalignant neoplasms." In contrast, "malignant neoplasms" are generally poorly differentiated (anaplasia) and characteristically rapidly grow with progressive infiltration, invasion, and destruction of surrounding tissues. In addition, malignant neoplasms generally have the ability to metastasize to the distal site. The terms "metastasis," "metastasis," or "metastasis" mean the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue, and the primary or original tumor. Is typically identifiable by the presence of "secondary tumors" or "secondary cell clusters" that are histological and are not histological in the organ or tissue in which the secondary (metastatic) tumor is located.

In some embodiments, the disease to be treated is cancer.
The term "cancer" refers to a class of disease characterized by the development of abnormal cells that have the ability to grow out of control, invade normal body tissue and destroy it.

In some embodiments, the cancer is head and neck cancer (eg, head and neck squamous epithelial cell carcinoma (SCCHN), adenoid cystic carcinoma).

In some embodiments, the cancer is an oral cancer (eg, buccal oral cancer, lip cancer, tongue cancer, mouth cancer, pharynx cancer, hypopharyngeal (hypopharynx) cancer (eg). , Hypopharyngeal cancer), pharyngeal cancer (eg, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), salivary gland cancer).

In some embodiments, the cancer is esophageal cancer (eg, esophageal squamous cell carcinoma, esophageal adenocarcinoma, valet adenocarcinoma, esophageal leiomyosarcoma).

In some embodiments, the cancer is gastrointestinal cancer (eg, anal cancer, colorectal cancer (eg, colon cancer, rectal cancer, colorectal adenocarcinoma), bile sac cancer, gastric cancer (eg, colon cancer, rectal cancer, colorectal adenocarcinoma). Examples include gastric cancer (eg, gastric adenocarcinoma), gastrointestinal interstitial tumor (GIST), small bowel cancer (eg, wormdrop cancer, small intestine cancer, eg, small intestine adenocarcinoma), small intestine. (Small intestine), large intestine (large bowel) cancer, large intestine (large intestine) cancer).

In some embodiments, the cancer is cardiovascular cancer (eg, primary heart tumor, angiosarcoma (eg, lymphangiosarcoma, angiosarcoma, angiosarcoma), endothelial sarcoma (eg, caposarcoma, multiple occurrences). Idiopathic angiosarcoma), cardiac mucinoma, cardiac angiosarcoma).

In some embodiments, the cancer is lung cancer (eg, bronchial cancer (eg, bronchogenic cancer, bronchial adenoma), alveolar cancer, mesenteric tumor, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC). ), Lung adenocarcinoma, chondricular erroneous tumor, papillary adenocarcinoma).

In some embodiments, the cancer is urogenital cancer (eg, bladder cancer (eg, urinary epithelial cancer), urinary tract cancer, kidney cancer (eg, nephroblastoma, also known as Wilms tumor, renal cells). Cancer), testicular cancer (eg, sperm epithelioma, testicular embryonic cancer), embryonic cell cancer, prostate cancer (eg, prostate adenocarcinoma), penis cancer (eg, penis and scrotum Paget's disease) )).

In some embodiments, the cancer is a gynecological cancer (eg, breast cancer (eg, breast adenocarcinoma, breast papillary cancer, mammary cancer, breast medulla cancer, triple). Negative breast cancer, HER-2 positive breast cancer, HER2-negative breast cancer), endometrial cancer (eg, uterine cancer (eg, uterine sarcoma, chorionic villus cancer), endometrial cancer), cervical cancer (eg) Cervical adenocarcinoma), ovarian cancer (eg, cyst adenocarcinoma, ovarian embryo cancer, ovarian adenocarcinoma), embryonic cell cancer, genital cancer (eg, genital Paget's disease), vagina Cancer, oviduct cancer).

In some embodiments, the cancer is hematopoietic cancer (eg, leukemia (eg, acute lymphocytic leukemia (ALL)) (eg, B-cell ALL, T-cell ALL), acute myelofibrotic leukemia (AML) ( Examples include B-cell AML, T-cell AML), chronic myelofibrotic leukemia (CML) (eg, B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (eg, B-cell CLL, T-cell). CLL)); lymphoma (eg, Hodgkin's lymphoma (HL) (eg, B-cell HL, T-cell HL)), non-Hodikin's lymphoma (NHL) (eg, B-cell NHL, eg, diffuse large cell lymphoma (eg, diffuse large cell lymphoma) DLCL) (eg, diffuse large B-cell lymphoma)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B cells Lymphoma (eg, mucosal-related lymphoid tissue (MALT) lymphoma, muscular marginal zone B-cell lymphoma, peri-spleen B-cell lymphoma), primary mediastinal B-cell lymphoma, Berkit lymphoma, lymphocytic cell lymphoma (ie) , Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, T cell NHL, For example, precursor T-lymphocytic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (eg, cutaneous T-cell lymphoma (CTCL) (eg, myelofibrosis, Cesarly syndrome)), vascular immunoblasts Sexual T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, undifferentiated large-cell lymphoma); heavy chain disease (eg, alpha chain disease, gamma chain) Disease, Mu Chain Disease); Myeloproliferative Disorder (MPD) (eg, True Erythrocytosis (PV), Essential Thrombocytopenia (ET), Idiopathic Myelofibrosis (AMM), Also known as Myelofibrosis (MF) ), Chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophil leukemia (CNL), hypereophilic syndrome (HES)); multiple myelofibrosis (MM); plasma cell neoplasia (Familiar hypereophilic hyperoculocytosis; inflammatory myelofibrosis; immune cell amyloidosis). In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia (ALL). In some embodiments, the cancer is an early T cell precursor (ETP) -acute lymphoblastic leukemia (ALL).

In some embodiments, the cancer is liver cancer (eg, hepatocellular carcinoma (HCC) (eg, hepatocellular carcinoma, hepatoblastoma, hepatocellular adenoma), malignant hepatoma, hemangiomas, biliary tract cancer (eg, eg). As for bile duct cancer)).

In some embodiments, the cancer is a musculoskeletal cancer (eg, bone cancer (eg, rhabdomyosarcoma, rhabdomyosarcoma, malignant fibrous histocytoma, Ewing sarcoma, chondrosarcoma, malignant giant cell tumor, chondrosarcoma). Chondrosarcoma, osteochondroma, benign chondrosarcoma, chondrosarcoma, chondromyxofibroma, myelodystrophy syndrome (MDS)), muscle cancer (eg, rhabdomyosarcoma (eg, rhabdomyosarcoma) rhabdomyosarcoma), rhabdomyosarcoma), connective tissue cancer, synovial tumor).

In some embodiments, the cancer is a nervous system cancer (eg, brain cancer (eg, stellate cell tumor, granuloblastoma, glioma (eg, stellate cell tumor, oligodendro glioma)). , Glioblastoma, polymorphic glioblastoma, medullary blastoma, coat tumor, germoma (ie, pine fruit tumor), oligodendro glioma, schwannoma, retinal blastoma, congenital tumor, cranial pharynx Tumors), spinal cord cancer, gliomas (eg, gliomas (NF) types 1 and 2, schwannomas), glioblastomas, undifferentiated neuroexoblastomas (PNTs), medullary Membrane cancer (eg, medullary carcinoma, medullary sarcoma, glioma), skull cancer, acoustic neuroma, schwannoma, hemangioblastoma, eye cancer (eg, intraocular melanoma, retinal blastoma) )). In some embodiments, the disease to be treated is a brain tumor. In some embodiments, the disease is pleomorphic astrocytoma (PXA). In some embodiments, the disease is pediatric pleomorphic astrocytoma (PXA).

In some embodiments, the cancer is endocrine / exocrine cancer (eg, thyroid cancer (eg, papillary thyroid cancer, follicular thyroid cancer; thyroid medullary cancer, multiple endocrine neoplasia type 2A, multiple endocrine). Neoplastic type 2B, familial medullary thyroid cancer, brown cell tumor, paraganglioma), pancreatic cancer (eg, pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor, tubular adenocarcinoma , Insulinoma, glucagonoma, bipoma), adrenal cancer, neuroendocrine cancer (eg, gastrointestinal / pancreatic neuroendocrine tumor (GEP-NET), cartinoid tumor), lipocardial cancer, sweat adenocarcinoma). In some embodiments, the cancer is a sweat gland cancer (eg, a sweat gland cancer).

In some embodiments, the cancer is a skin cancer (eg, squamous cell carcinoma (SCC), keratinized spinous cell carcinoma (KA), melanoma, basal cell carcinoma (BCC), skin fibroma).

In some embodiments, the cancer is a soft tissue cancer (eg, intraepithelial neoplasia, epithelial cancer, epithelial sarcoma, adenocarcinoma, adenoma, fibrosarcoma, fibrosarcoma, liposarcoma, lipoma, mucinoma, teratoma). Is.

In some embodiments, the cancer is a rare cancer. The term "rare cancer" means cancer that occurs in a relatively small number of patients. Rare cancers are, but are not limited to, sarcomas (eg, soft tissue sarcoma, liposarcoma, uterine sarcoma, smooth muscle sarcoma, mucinous fibrosarcoma, osteosarcoma, hemangiosarcoma, Ewing sarcoma, synovial sarcoma, rhabdomyosarcoma). , Malignant lymphoma, thoracic adenocarcinoma (eg, sarcoma), sarcoma, gastrointestinal stromal tumor (GIST), neuroendocrine cancer, eye cancer, brain tumor, bone soft tissue tumors, skin Includes sarcomas and sarcomas.

Examples of proliferative disorders, cancers, and tumors are provided herein. In certain aspects of the methods provided herein, the cancer is head and neck cancer (eg, squamous cell carcinoma of the head and neck, adenoid cystic carcinoma, oral cancer, throat cancer, salivary gland cancer, etc. Tongue cancer). In some embodiments, the cancer is breast cancer (eg, HER2-positive breast cancer, HER2-negative breast cancer, triple-negative breast cancer). In some embodiments, the cancer is colorectal cancer (eg, colon cancer). In some embodiments, the cancer is esophageal cancer (eg, esophageal adenocarcinoma). In some embodiments, the cancer is uterine cancer (eg, uterine sarcoma). In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is a sarcoma (eg, uterine sarcoma, fibrosarcoma, angiosarcoma, synovial sarcoma, soft tissue sarcoma, endometrial sarcoma). In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is lung cancer (eg, non-small cell lung cancer). In some embodiments, the cancer is bladder cancer (eg, urothelial cancer). In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is small intestine cancer (eg, small intestine cancer, eg, small intestine adenocarcinoma). In some embodiments, the cancer is a sweat gland cancer (eg, a sweat gland cancer). In some embodiments, the cancer is a rare cancer.

Combination Therapies In addition to administration as monotherapy, the compounds provided herein (eg, compounds represented by formulas (I), (II), (III), and (IV)) are other Can be administered in combination with a therapeutic agent or treatment modality of. In some embodiments, the compound is administered in combination with an anti-cancer agent. "Anti-cancer agents" include biotherapeutic anti-cancer agents and chemotherapeutic agents.

Examples of biotherapeutic anti-cancer agents are, but are not limited to, interferon, cytokines (eg, tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulators. And / or immunomodulators (eg IL-1, 2, 4, 6, or 12), immune cell growth factors (eg GM-CSF), and antibodies (eg Herceptin (trastuzumab), T- DM1, Avastin (vebashizumab), arbitux (cetuximab), vectibix (panitummab), rituximab (rituximab), bexal (tositumomab), and other antibodies described above.

Illustrated chemotherapeutic agents include, but are not limited to, anti-estrogen agents (eg, tamoxyphen, laroxifen, and megestrol), LHRH agonists (eg, goscrclin and leuprolide), anti-androgen agents (eg, flutamide and). Vicartamide), photodynamic treatment (eg vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypoclerin A (2BA-2-DMHA)), nitrogen mustard (eg cyclo) Phosphamide, iphosphamide, trophosphamide, chlorambusyl, estramustin, and melphalan), nitrosourea (eg carmustin (BCNU) and romustin (CCNU)), alkylsulfonate (eg busulfan and treosulfan), triazen (eg) Examples include dacarbazine, temozolomid), platinum-containing compounds (eg cisplatin, carboplatin, oxaliplatin), binca alkaloids (eg bincristin, vinblastin, bindesin, and binorerbin), taxoids (eg paclitaxel or paclitaxel equivalents, eg nanoparticles). Albumin-binding paclitaxel (Abraxane), docosahexaenoic acid-binding paclitaxel (DHA-paclitaxel, taxaoplexin), polyglutamate-linked paclitaxel (PG-paclitaxel, paclitaxel polygourmetax, CT-2103, geotax (XYOTAX)), tumor activation pro Drug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to erbB2 recognition peptide EC-1), and glucose-conjugated paclitaxel, eg, 2'-paclitaxel methyl 2-Glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (eg etopocid, etopocid phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, chrysnator, mitomycin C), anti Metabolites, DHFR inhibitors (eg methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibits Tar (eg mycophenolic acid, thiazofulin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (eg hydroxyurea and deferroxamine), uracil analogs (eg 5-fluorouracil (5-FU), floxuridine, doxiflulysin, etc. Larchitrexed, Tegafur-uracil, capesitabin), citocin analogs (eg citalabine (ara C), citocin arabinoside, and fludalabine), purine analogs (eg mercaptopurine and thioguanin), vitamin D3 analogs (eg EB) 1089, CB 1093, and KH 1060), isoprenylation inhibitor (eg robastatin), dopamine neurotoxin (eg 1-methyl-4-phenylpyridinium ion), cell cycle inhibitor (eg staurosporin), actinomycin (eg staurosporin) Examples include actinomycin D, dasatinib), bleomycin (eg bleomycin A2, bleomycin B2, pepromycin), anthracycline (eg daunorbisin, doxorubicin, pegulated liposome doxorubicin, idalubicin, epirubicin, pyrarbisin, sorbicin, mitoxanthrone) , MDR Inhibitor (eg Bellapamil), Ca ²⁺ ATPase Inhibitor (eg Tapsigargin, Imatinib, Salidamide, Lenalidemid, Tyrosine Kinase Inhibitor (eg Axitinib (AG013736), Bostinib (SKI-606), Sedilanib (Recentin ™) , AZD2171), dasatinib (Splicel®, BMS-354825), elrotinib (Tarceva®), gefitinib (Iressa®), imatinib (Gleevec®, CGP57148B, STI-571), Lapatinib (Tykerb®, Tybarb®), Restaultinib (CEP-701), Neratinib (HKI-272), Nirotinib (Tasigna®), Semaxanib (Semaxinib, SU5416), Sunitinib (Sutent) Trademarks), SU11248), Toceranib (Paradia®), Bandetanib (Zactima®, ZD6474), Vataranib (PTK787, PTK / ZK), Trustuzumab (Herceptin®) ), Bebasizumab (Avastin®), Lithuximab (Rituxan®), Cetuximab (Arbitux (Registered Trademark)), Panitumumab (Vectibix®), Ranibizumab (Lucentis®), Nirotinib (Tasigna®), Sorafenib (Nexavar®), Everolimus (Affinitol®), Alemtuzumab (Campus®), Gemtuzumab ozogamicin (Myrotag®), Everolimus (Tricell®), ENMD-2076, PCI-32765, AC220, Dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK ™), SGX523, PF-04217903, PF- 02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-264833327, MGCD265, DCC-2036, BMS-690154, CEP-11981, Cetuximab (AV-951), OSI-930, MM-121, XL-184, XL-647, and / or XL228), proteasome inhibitors (eg, voltezomib (Velcade)), mTOR inhibitors (eg, rapamycin, everolimus (eg, rapamycin, everolimus) CCI-779), Everolimus (RAD-001), Lidahololimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Novartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer) ), SF1126 (Semafore) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetlexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin , Porphyromycin, Melfaran, leurosidine, leurosin, chlorambusil, trabectedin, procarbazine, discodelmolide, carminomycin, Includes aminopterin, and hexamethylmelamine.

In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof are used in combination with radiation therapy (RT). In some embodiments, the compound is administered in combination with surgery. In some embodiments, the compound is administered in combination with immunotherapy.

For example, the compounds of the invention can be administered in combination with other therapeutic agents such as anti-EGFR therapy, anti-HER2 therapy, anti-PD-1 therapy, anti-PD-L1 therapy, or irradiation therapy.

In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof are anti-EGFR therapeutics (eg, anti-EGFR monoclonals such as cetuximab). It is administered in combination with an antibody (mAb)). For example, what is provided herein is a compound provided herein, or a pharmaceutically acceptable salt or isotope label thereof, in combination with anti-EGFR (epidermal growth factor receptor) mAb therapy. A method of treating head and neck squamous cell carcinoma (SCCHN) in a subject, comprising administering to the subject the derivative, or pharmaceutical composition thereof. In some embodiments, the anti-EGFRmAb is cetuximab (CTX).

In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof are anti-HER2 therapeutics (eg, anti-HER2 monoclonals such as trastuzumab). It is administered in combination with an antibody (mAb)). For example, what is provided herein is a compound provided herein, or a pharmaceutically acceptable salt or isotope label thereof, in combination with HER2 (Human Epidermal Growth Factor Receptor) mAb therapy. A method of treating breast cancer in a subject in need thereof, comprising administering to the subject the resulting derivative, or pharmaceutical composition thereof. In some embodiments, the anti-HER2mAb is trastuzumab.

In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts or isotope-labeled derivatives thereof, or pharmaceutical compositions thereof are anti-PD-1 or anti-PD-L1 therapies (eg, by way of example. , Anti-PD-1 or anti-PD-L1 monoclonal antibody). For example, what is provided herein is a compound provided herein, or pharmaceutically acceptable thereof, in combination with anti-PD-1 or anti-PD-L1 therapy (eg, mAb therapy). A method of treating colorectal cancer in a subject in need thereof, comprising administering to the subject a salt or isotope-labeled derivative thereof, or a composition thereof.

Example Compound Synthesis General Procedures and Methods The compounds according to the invention can be produced by the methods described in the examples below. However, these examples are for illustrative purposes only, and the compounds according to the invention are by no means limited to the specific examples described below.

In the example, unless otherwise specified, the purification silica gel used for silica gel column chromatography is a Hi-Flash ™ column (silica gel, 30 μm 60 Å or 40 μm 60 Å, Yamazen Co., Ltd.). , NH silica gel The silica gel for purification used for column chromatography was Chromatorex NH silica gel (Fuji Silicia Chemical Co., Ltd.). For analytical thin layer chromatography, TLC silica gel 60 F ₂₅₄ , layer thickness 0.25 mm (Merck) or Chromatorex TLC NH silica gel F ₂₅₄ , layer thickness 0.25 mm (Fuji Silysia Chemical Ltd.) ) Was used. The TLC plate was stained and visualized with a p-anisaldehyde stain, a phosphomolybdic acid stain, or a Hanesian stain.

All moisture sensitive reactions were carried out in an inert atmosphere. Reagents and solvents were of commercial grade and were used as supplied unless otherwise noted.

NMR spectra were recorded with a JEOL ECZ500R (500MHz), JEOL ECZ400S (400MHz), Varian Inova 500 (500MHz), Varian Mercury 400 (400MHz), or Bruker Avance (600MHz) spectrometer. Chemical shifts are reported in parts per million (ppm). ^{1 For the 1} H NMR spectrum (CDCl ₃ , C ₆ D ₆ , and / or CD ₃ OD), the residual solvent peak was set to an internal reference ( _{7.27 ppm in CDCl 3} ; 7.16 ppm in C ₆ D ₆ ; _{3 in} CD 3 OD). It was used as .31 ppm).

Analytical mass spectra (MS) results were obtained using a Waters Acquity UPLC equipped with a single quadrupole detector (SQ Detector2) or LTQ Orbitrap XL ™ (Thermo Scientific).

High performance liquid chromatography (HPLC) was performed using a Shimadzu LC-10AD with a UV spectrophotometer (200 nm, Shimadzu SPD-10A).

The abbreviations used herein are: AIBN: 2,2'-azobis (isobutylaluminum); Alloc: allyloxycarbonyl; 9-BBN: 9-borabicyclo [3.3.1]. Nonan; Bu ₃ SnH: Tri-normal-butyltin hydride; (+)-CSA: (1S)-(+) -10-camparsulfonic acid; DMAP: 4-dimethylaminopyridine; DCM: dichloromethane; DDQ: 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone; DIBAL: diisobutylaluminum hydride; DMF: N, N- dimethylformamide; DMSO: dimethyl sulfoxide; _Et 3 N: triethylamine; EtOAc: ethyl acetate; HF- Py: hydrogen fluoride pyridine; HPLC: fast liquid chromatography; IPA: isopropyl alcohol; MeCN: acetonitrile; MeOH: methanol; MPM: para-methoxybenzyl; PPh ₃ : triphenylphosphine; t-BuOH: tert-butyl alcohol; tBuLi: tert-butyl lithium; TBME: methyl-tert-butyl ether; TBAF: tetrabutylammonium fluoride; TBS: tert-butyldimethylsilyl; THF: tetrahydrofuran; TMS: trimethylsilyl; Ts: para-toluenesulfonyl.

例１
（４ａＲ，５ａＳ，６Ｒ，８ａＳ，９ａＲ）−２，２−ジ−ｔｅｒｔ−ブチル−６−メチルオクタヒドロフロ［２’，３’：５，６］ピラノ［３，２−ｄ］［１，３，２］ジオキサシリン−７−オール

The synthetic intermediates disclosed herein are considered part of the present invention.
Scheme A-1; Preparation of Compound A-7

Example 1
(4aR, 5aS, 6R, 8aS, 9aR) -2,2-di-tert-butyl-6-methyloctahydroflo [2', 3': 5,6] Pyrano [3,2-d] [1, 3,2] Dioxacillin-7-ol

Compound A-1 obtained by the method described in Organic Letters (2009), 11 (2), 409-412 under a nitrogen atmosphere: (4aR, 5aS, 6R, 8aS, 9aR) -2,2-di-tert -Butyl-6-methylhexahydroflo [2', 3': 5,6] pyrano [3,2-d] [1,3,2] dioxacillin-7 (8aH) -one (A-1 18. DIBAL (70.2 mL, 70.2 mmol, 1.0 M toluene solution) was added to a solution of 5 g, 54.0 mmol) (CAS number; 1095280-04-8) at −78 ° C. in toluene (275 mL) over 30 minutes. did. The reaction mixture was then stirred at −78 ° C. After 90 minutes, the reaction was carefully quenched with MeOH (4.37 mL) at −78 ° C. and then the cooling bath was removed. A saturated aqueous solution of potassium sodium tartrate tetrahydrate (300 mL) was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. The reaction mixture was poured into a separatory funnel and then the layers were separated. The aqueous layer was extracted with EtOAc (300 mL). The combined organic extracts were washed with saturated brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude lactol was used in the next reaction without purification.
Example 2
(4aR, 6S, 7S, 8aR) -6-((S) -Pig-3-en-2-yl) -2,2-di-tert-butylhexahydropyrano [3,2-d] [1 , 3, 2] Dioxacillin-7-ol (Compound A-2)

Potassium tert-butoxide (17.27 g, 153.9 mmol) was added to a suspension of methyltriphenylphosphonium bromide (73.30 g, 205.2 mmol) in THF (200 mL) under a nitrogen atmosphere at −5 ° C. for 10 minutes. And then stirred at −5 ° C. for 60 minutes. The solution of crude lactol described in Example 1 in THF (40 mL) was transferred to the reaction mixture at −5 ° C. for 10 minutes and then stirred at −5 ° C. for 1 hour and at room temperature for 1 hour. The reaction mixture was quenched with ice water (400 mL), then diluted with TBME (400 mL) and then the layers were separated. The aqueous layer was extracted with TBME (400 mL). The combined organic extracts were washed with saturated brine (400 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was suspended in heptane / EtOAc = 1/1 (100 mL). The resulting suspension was filtered and washed with heptane / EtOAc = 1/1 (100 mL) to remove triphenylphosphine-derived material. The filtrate was then concentrated under reduced pressure. The residue was subjected to silica gel (400 g, Silica Gel 60, spherical, 40-50 μm, Kanto Chemical) flash column chromatography using EtOAc / heptane, and the title compound (Compound A-2, 16.7 g, 90%) was subjected to flash column chromatography. (Yield) was obtained.

¹ H NMR (400 MHz, chloroform-d) δ ppm 1.03 (d, J = 6.8 Hz, 3 H) 1.05 (s, 9 H) 1.07 (s, 9 H) 1.75 (dt, J = 14.5, 3.0 Hz, 1 H) 2.37 (dt, J = 14.5, 2.9 Hz, 1 H) 2.65 --2.76 (m, 1 H) 3.03 (dd, J = 9.8, 1.0 Hz, 1 H) 3.31 (m, 1 H) 3.69 (d) , J = 15.0 Hz, 1 H) 3.75 --3.79 (m, 1 H) 4.16 --4.31 (m, 2 H) 4.41 (t, J = 2.9 Hz, 1 H) 4.95 --5.09 (m, 2 H) 6.02 ( ddd, J = 17.3, 10.5, 6.3 Hz, 1 H).
Example 3
(4aR, 6S, 7S, 8aR) -6-((S) -Pig-3-en-2-yl) -2,2-di-tert-butyl-7-((tert-butyldimethylsilyl) oxy) Hexahydropyrano [3,2-d] [1,3,2] dioxacillin (Compound A-3)

Compound A-2 according to Example 2: (4aR, 6S, 7S, 8aR) -6-((S) -but-3-en-2-yl) -2,2-di-tert- under a nitrogen atmosphere. Butylhexahydropyrano [3,2-d] [1,3,2] dioxacillin-7-ol (9.85 g, 28.8 mmol) in a solution of 2,6-lutidine in DCM (150 mL) at 0 ° C. (6.68 mL, 57.5 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (9.25 mL, 40.3 mmol) were added. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether. The organic layer was washed with 0.5N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution, and then saturated brine. The combined organic layers were dried over magnesium sulphate, _{filtered (using a small amount of SiO 2} ) and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% to 15% EtOAc / heptane to give the title compound (Compound A-3, 12.0 g, 91% yield).

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.10 (s, 3 H) 0.19 (s, 3 H) 0.91 (s, 9 H) 0.96 (d, J = 6.3 Hz, 3 H) 1.02 (s, 3 H) 9 H) 1.06 (s, 9 H) 1.73 (dt, J = 15.0, 4.0 Hz, 1 H) 2.26 (dt, J = 15.0, 2.5 Hz, 1 H) 2.66 --2.74 (m, 1 H) 2.95 (dd) , J = 9.5, 2.2 Hz, 1 H) 3.17 (m, 1 H) 3.81 --3.81 (m, 1 H) 4.12 --4.22 (m, 2 H) 4.24 (t, J = 2.7 Hz, 1 H) 4.93- 5.06 (m, 2 H) 6.08 (ddd, J = 17.3, 10.5, 6.3 Hz, 1 H).
Example 4
(2R, 3R, 5S, 6S) -6-((S) -Pig-3-en-2-yl) -5-((tert-butyldimethylsilyl) oxy) -2- (hydroxymethyl) tetrahydro-2H -Pyran-3-ol (Compound A-4)

Compound A-3: (4aR, 6S, 7S, 8aR) -6-((S) -but-3-en-2-yl) -2,2-di-tert- according to Example 3 under a nitrogen atmosphere. MeCN (120 mL) at -10 ° C. of butyl-7-((tert-butyldimethylsilyl) oxy) hexahydropyrano [3,2-d] [1,3,2] dioxacillin (12 g, 26.3 mmol). To the solution of DCM (40 mL) was added a solution of HF-pyridine (4.0 mL) and pyridine (20 mL) premixed in 20 mL of MeCN. The reaction mixture was stirred at −10 ° C. for 15 minutes and then at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution at 0 ° C., diluted with DCM, then the layers were separated. The aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated brine. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 15% to 60% EtOAc / heptane to give the title compound (Compound A-4, 8.4 g, quantitative yield).

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.13 (s, 3 H) 0.19 (s, 3 H) 0.94 (s, 9 H) 0.96 (d, J = 6.8 Hz, 3 H) 1.72 (dt, 3 H) J = 14.6, 2.9 Hz, 1 H) 2.15 (dd, J = 9.8, 2.4 Hz, 1 H) 2.23 (dt, J = 14.6, 2.9 Hz, 1 H) 2.55 --2.65 (m, 1 H) 3.03 (d) , J = 9.8 Hz, 1 H) 3.41 --3.46 (m, 1 H) 3.49 (d, J = 11.7 Hz, 1 H) 3.62 --3.72 (m, 2 H) 3.92 (ddd, J = 11.7, 8.3, 2.4 Hz, 1 H) 4.02 (t, J = 2.7 Hz, 1 H) 5.01 --5.12 (m, 2 H) 5.93 (ddd, J = 17.4, 10.4, 7.3 Hz, 1 H).
Example 5
(((2S, 3S, 5R, 6R) -2-((S) -but-3-en-2-yl) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran -3,5-diyl) bis (oxy)) bis (tert-butyldimethylsilane) (Compound A-5)

Compound A-4: (2R, 3R, 5S, 6S) -6-((S) -but-3-en-2-yl) -5-((tert-butyldimethyl) according to Example 4 under a nitrogen atmosphere. 2.6-Lutidine (1.83 mL, 15.3 mL) in a solution of silyl) oxy) -2- (hydroxymethyl) tetrahydro-2H-pyran-3-ol (997 mg, 3.15 mmol) at 5 ° C. in DCM (10 mL). 8 mmol) and tert-butyldimethylsilyltrifluoromethanesulfonate (2.17 mL, 9.45 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with diethyl ether, quenched with saturated aqueous sodium hydrogen carbonate solution, and then the layers were separated. The combined organic extracts were washed continuously with 0.5N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution, and then saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica gel flash column chromatography using 0% ~5% EtOAc / Heptane (containing 1% Et ₃ N), the title compound (Compound A-5,1.69g, 98% yield) It was.

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.02 --0.08 (m, 15 H) 0.11 (s, 3 H) 0.89 (s, 9 H) 0.90 --0.92 (m, 18 H) 0.94 (d, J) = 6.8 Hz, 3 H) 1.82 (dt, J = 14.9, 4.8 Hz, 1 H) 2.00 (dt, J = 14.9, 2.9 Hz, 1 H) 2.62 --2.72 (m, 1 H) 2.93 (dd, J = 9.3, 2.0 Hz, 1 H) 3.27 --3.34 (m, 1 H) 3.66 --3.79 (m, 3 H) 3.83 --3.97 (m, 1 H) 4.91 --5.07 (m, 2 H) 6.11 (ddd, J = 17.3, 10.7, 6.1Hz, 1 H).
Example 6
(S) -3-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro- 2H-pyran-2-yl) butane-1-ol (Compound A-6)

Compound A-5 according to Example 5: (((2S, 3S, 5R, 6R) -2-((S) -but-3-en-2-yl) -6-(((tert-butyldimethylsilyl)). ) Oxy) methyl) tetrahydro-2H-pyran-3,5-diyl) bis (oxy)) bis (tert-butyldimethylsilane) (1.32 g, 2.42 mmol) in a solution in THF (10 mL) at 0 ° C. 9-BBN (9.69 mL, 0.5 M THF solution, 4.84 mmol) was added. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 1.5 hours. A 3.0 M aqueous sodium hydroxide solution (3 mL, 9.00 mmol) and hydrogen peroxide (35% aqueous solution, 3 mL) were added to the reaction mixture at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite solution and then the layers were separated. The aqueous layer was extracted with EtOAc (3 times). The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% to 20% EtOAc / heptane to give the title compound (Compound A-6, 1.36 g, 100% yield).

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.03 (s, 3 H) 0.05 --0.08 (m, 12 H) 0.10 (s, 3 H) 0.88 (d, J = 6.8 Hz, 3 H) 0.89- 0.93 (m, 27 H) 1.55 --1.65 (m, 1H) 1.82 (dt, J = 15.4, 4.4 Hz, 1 H) 1.87 --1.96 (m, 1 H) 1.97 --2.03 (m, 1 H) 2.17-2.26 (m, 1H) 2.67 (dd, J = 7.8, 3.9 Hz, 1 H) 2.98 ---3.10 (m, 1 H) 3.34 --3.40 (m, 1 H) 3.59 --3.86 (m, 6 H)
ESI-MS (m / z): 563.64 [M + H] ⁺ , 585.62 [M + Na] ⁺
Example 7
(S) -3-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro- 2H-pyran-2-yl) butanal (Compound A-7)

Compound A-6: (S) -3-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-() according to Example 6 under a nitrogen atmosphere. Sodium hydrogen carbonate (41) in a solution of ((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) butane-1-ol (1100 mg, 1.954 mmol) at 5 ° C. in DCM (30 mL). 0.0 mg, 0.49 mmol) and des-martin peryodinane (1077 mg, 2.54 mmol) were added. The reaction mixture was stirred at room temperature. After 3 hours, the reaction mixture was diluted with DCM, quenched with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium sulfite solution, and then the layers were separated. The aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% -25% EtOAc / heptane to give the title compound (Compound A-7, 950 mg, 87% yield).

例８
（２Ｓ，３Ｓ）−３−（（４−メトキシベンジル）オキシ）−２−メチル−５−（トリメチルシリル）ペンタ−４−イン−１−イル４−メチルベンゼンスルホネート（化合物Ｂ−２）

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.00 (s, 3 H) 0.03 --0.08 (m, 12 H) 0.11 (s, 3 H) 0.88 (s, 9 H) 0.91 --0.92 (m, 21H) ) 1.82 (dt, J = 15.0, 4.5 Hz, 1 H) 2.01 (dt, J = 15.0, 2.5 Hz, 1 H) 2.28 (ddd, J = 16.0, 7.3, 2.4 Hz, 1 H) 2.53 -2.58 (m) , 1 H) 2.74 (ddd, J = 16.0, 5.5, 2.0 Hz, 1 H) 2.94 (dd, J = 9.0, 1.7 Hz, 1 H) 3.29 (td, J = 5.9, 2.0 Hz, 1 H) 3.68 ( d, J = 5.9 Hz, 2 H) 3.75 --3.82 (m, 1 H) 3.82 --3.90 (m, 1 H) 9.73 (t, J = 2.4 Hz, 1 H).
Scheme B; Preparation of compound B-3

Example 8
(2S, 3S) -3-((4-Methoxybenzyl) oxy) -2-methyl-5- (trimethylsilyl) penta-4-in-1-yl 4-methylbenzenesulfonate (Compound B-2)

Compound B-1 obtained by the method described in WO 9317690 A1 / US 5436238 A under a nitrogen atmosphere: (2S, 3S) -3-((4-methoxybenzyl) oxy) -2-methyl-5- (trimethylsilyl) ) pent-4-yn-1-ol (11.08g, 36.15mmol) (CAS number; in DCM (330 mL) solution of _{157323-41-6), Et 3 N (12.6mL} , 90.4mmol) and Para-toluenesulfonyl chloride (8.27 g, 43.4 mmol) was added at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel (Silica Gel 60, spherical, 40-50 μm, Kanto Chemical) flash column chromatography using 0% to 10% EtOAc / heptane to yield the title compound (Compound B-2, 17.7 g, 93%). Rate) was obtained.

^{1 1} H NMR (500 MHz, chloroform-d) δ ppm 0.17 (s, 9 H) 1.02 (d, J = 6.8 Hz, 3 H) 2.10 --2.18 (m, 1 H) 2.44 (s, 3 H) 3.82 ( s, 3 H) 3.99 (d, J = 6.8 Hz, 1 H) 4.04 --4.07 (m, 2 H) 4.33 (d, J = 11.2 Hz, 1 H) 4.66 (d, J = 11.2 Hz, 1 H) 6.87 (d, J = 8.3 Hz, 2 H) 7.21 (d, J = 8.3 Hz, 2 H) 7.33 (d, J = 8.8 Hz, 2 H) 7.77 (d, J = 8.8 Hz, 2 H).
Example 9
((3S, 4R) -5-iodo-3-((4-methoxybenzyl) oxy) -4-methylpent-1-in-1-yl) trimethylsilane (Compound B-3)

Compound B-2: (2S, 3S) -3-((4-methoxybenzyl) oxy) -2-methyl-5- (trimethylsilyl) penta-4-in-1-yl according to Example 8 under a nitrogen atmosphere. Sodium iodide (7.49 g, 50.0 mmol) was added to a solution of 4-methylbenzenesulfonate (17.7 g, 38.4 mmol) in DMF (360 mL) at room temperature. The reaction mixture was stirred at 80 ° C. for 2 hours. 2.0 g of sodium iodide was further added to the reaction mixture. The reaction was stirred at 80 ° C. for 1.5 hours and then cooled to room temperature. The mixture was diluted with diethyl ether, washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash column chromatography on silica gel (Silica Gel 60, spherical, 40-50 μm, Kanto Chemical) with 10% to 20% EtOAc / Heptane to the title compound (Compound B-3, 14.3 g, 89%). (Yield) was obtained.

例１０
（２Ｓ，６Ｓ，７Ｓ）−２−（（２Ｓ，３Ｓ，５Ｒ，６Ｒ）−３，５−ビス（（ｔｅｒｔ−ブチルジメチルシリル）オキシ）−６−（（（ｔｅｒｔ−ブチルジメチルシリル）オキシ）メチル）テトラヒドロ−２Ｈ−ピラン−２−イル）−７−（（４−メトキシベンジル）オキシ）−６−メチル−９−（トリメチルシリル）ノナ−８−イン−４−オール（化合物Ｃ−１）

^{1 1} H NMR (500 MHz, chloroform-d) δ ppm 0.21 (s, 9 H) 1.10 (d, J = 6.8 Hz, 3 H) 1.74 --1.84 (m, 1 H) 3.30 --3.37 (m, 2 H) 3.82 (s, 3 H) 3.96 (d, J = 7.3 Hz, 1 H) 4.44 (d, J = 11.2 Hz, 1 H) 4.73 (d, J = 11.2 Hz, 1 H) 6.89 (d, J = 8.8) Hz, 2 H) 7.30 (d, J = 8.8 Hz, 2 H).
Scheme C-1; Preparation of Compound C-8

Example 10
(2S, 6S, 7S) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy)) Methyl) tetrahydro-2H-pyran-2-yl) -7-((4-methoxybenzyl) oxy) -6-methyl-9- (trimethylsilyl) nona-8-in-4-ol (Compound C-1)

Compound B-3: ((3S, 4R) -5-iodo-3-((4-methoxybenzyl) oxy) -4-methylpent-1-in-1-yl) trimethyl according to Example 9 under an argon atmosphere. To a solution of silane (1408 mg, 3.382 mmol) at −78 ° C. in diethyl ether (25 mL) was added tert-butyllithium (1.61 M pentane solution, 4.11 mL, 6.62 mmol). The reaction mixture was stirred at −78 ° C. for 45 minutes. Compound A-7: (S) -3-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy)-) according to Example 7 in 5.0 mL of diethyl ether. 6-(((tert-Butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) butanal (825 mg, 1.47 mmol) was added to the reaction mixture at −78 ° C. The reaction mixture was stirred at −78 ° C. for 60 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% to 25% EtOAc / heptane to give the title compound (Compound C-1, 1167 mg, 93% yield).

^{1 1} H NMR (500 MHz, chloroform-d) δ ppm 0.00 --0.12 (m, 21 H) 0.15 --0.24 (m, 6 H) 0.82 --0.96 (m, 30 H) 1.03 (d, J = 6.3 Hz, 3H) ) 1.38 --1.55 (m, 1H) 1.68 --1.99 (m, 4 H) 2.10 --2.30 (m, 2 H) 2.76 --2.87 (m, 1 H) 3.15 (d, J = 9.75 Hz, 1 H) 3.33 - 3.38 (m, 1 H) 3.56 --4.02 (m, 9 H) 4.37 --4.50 (m, 1 H) 4.64 --4.78 (m, 1 H) 6.83 --6.88 (m, 2H) 7.23 --7.35 (m, 2H) ..
Example 11
(2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl)) Oxy) Methyl) Tetrahydro-2H-pyran-2-yl) -7-((4-Methoxybenzyl) oxy) -6-methyl-9- (tributylstannyl) nona-8-en-4-ol (Compound C) -3)

Compound C-1 according to Example 10: (2S, 6S, 7S) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-( ((Tert-Butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -7-((4-methoxybenzyl) oxy) -6-methyl-9- (trimethylsilyl) nona-8-in- Potassium carbonate (189 mg, 1.37 mmol) was added to a solution of 4-ol (1165 mg, 1.37 mmol) at 20 ° C. in MeOH (20 mL). The reaction mixture was stirred at 20 ° C. for 2 hours. The reaction mixture was diluted with EtOAc and quenched with saturated aqueous ammonium chloride solution, then the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% to 15% EtOAc / heptane to compound C-2: (2S, 6S, 7S) -2-((2S, 3S, 5R, 6R) -3,5- Bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -7-((4-methoxybenzyl) oxy)- 6-Methylnona-8-in-4-ol (1050 mg, 98% yield) was obtained. ESI-MS (m / z): 801.50 [M + Na] ⁺

Compound C-2 obtained above under a nitrogen atmosphere: (2S, 6S, 7S) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy)- 6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -7-((4-methoxybenzyl) oxy) -6-methylnona-8-in-4-ol ( Hydrogenated tri-normal-butyltin (2.5 mL, 9.36 mmol) and 2,2'-azobis (isobutyronitrile) (82 mg, 0) in a 20 ° C. toluene (15 mL) solution of 780 mg, 1.00 mmol). .50 mmol) was added. The reaction mixture was stirred at 90 ° C. for 15 minutes. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% to 15% EtOAc / heptane to give the title compound (Compound C-3, 970 mg, 91% yield).

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.02 --0.13 (m, 18 H) 0.84 --0.96 (m, 48 H) 1.22 --1.37 (m, 6 H) 1.47 --1.56 (m, 7 H) 1.72 --1.90 (m, 3 H) 1.95-2.03 (m, 1 H) 2.11 --2.28 (m, 2 H) 2.82 --2.86 (m, 1 H) 3.08 --3.15 (m, 1 H) 3.33 --3.40 (m, 1 H) 1 H) 3.43 --3.53 (m, 1 H) 3.58 --3.87 (m, 8 H) 4.25 --4.31 (m, 1 H) 4.49 --4.54 (m, 1 H) 5.83 (dd, J = 19.3, 7.6Hz, 1 H) 6.05 --6.13 (m, 1 H) 6.83 --6.90 (m, 2 H) 7.24 (d, J = 8.8 Hz, 2 H).
Example 12
(2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl)) Oxy) Methyl) Tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnona-8-en-4-one (Compound C-4)

Compound C-3: (2S, 6S, 7S) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) according to Example 11 under a nitrogen atmosphere. -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -7-((4-methoxybenzyl) oxy) -6-methyl-9- (tributylstannyl) Reaction of iodine (242 mg, 0.95 mmol) in DCM (6 mL) to 30 mL of DCM at 5 ° C. of nona-8-en-4-ol (970 mg, 0.91 mmol) until the mixture maintains iodine color. Added. The reaction mixture was quenched with saturated aqueous sodium sulfite solution to separate layers. The aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% -25% EtOAc / heptane (2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((2S, 3S, 5R, 6R) -3,5-bis tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-Methylnona-8-en-4-ol (768 mg, 93% yield) was obtained.

Under a nitrogen atmosphere, the above obtained (2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-( ((Tert-Butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnona-8-en-4-ol Sodium hydrogen carbonate (17.8 mg, 0.21 mmol) and des-martin peryodinane (485 mg, 1.14 mmol) were added to a solution of (768 mg, 0.85 mmol) in DCM (25 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM, quenched with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium sulfite solution, and then the layers were separated. The aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% to 20% EtOAc / heptane to give the title compound (Compound C-4, 776 mg, quantitative yield).

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.00 (s, 3 H) 0.03 --0.07 (m, 12 H) 0.10 (s, 3 H) 0.81 (d, J = 6.3 Hz, 3 H) 0.84 ( d, J = 6.3 Hz, 3 H) 0.89 (s, 9 H) 0.91 (s, 9 H) 0.92 (s, 9 H) 1.80 (dt, J = 15.0, 4.5 Hz, 1 H) 1.99 (dt, J) = 15.0, 2.5 Hz, 1 H) 2.17 (dd, J = 16.6, 10.2 Hz, 1 H) 2.20 --2.29 (m, 2 H) 2.43 --2.48 (m, 1 H) 2.54 (d, J = 12.7 Hz, 1 H) 2.87 (dd, J = 9.0, 1.7 Hz, 1 H) 2.99 (dd, J = 16.6, 2.9 Hz, 1 H) 3.27 (td, J = 5.8, 2.4 Hz, 1 H) 3.50 --3.56 (m) , 1 H) 3.66 --3.74 (m, 2H) 3.75 --3.78 (m, 1 H) 3.80 (s, 3 H) 3.81 --3.85 (m, 1 H) 4.26 (d, J = 11.7 Hz, 1 H) 4.50 (d, J = 11.7 Hz, 1 H) 6.26 (d, J = 14.6 Hz, 1 H) 6.42 (dd, J = 14.6, 7.8 Hz, 1 H) 6.87 (d, J = 8.3 Hz, 2 H) 7.21 (d, J = 8.3 Hz, 2 H). ESI-MS (m / z): 927.39 [M + Na] ⁺
Example 13
(2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6- (hydroxymethyl) tetrahydro-2H-pyran -2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnona-8-en-4-one (Compound C-5)

Compound C-4: (2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6) according to Example 12. -(((Tert-Butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnona-8-ene-4 (1S)-(+) -10-camphor in a solution of −ON (600 mg, 0.66 mmol) in THF (5.0 mL), IPA (5.0 mL), t-BuOH (5.0 mL) at 4 ° C. Sulfonic acid (154 mg, 0.66 mmol) was added. The reaction mixture was stirred at 4 ° C. for 20 hours. The reaction mixture was diluted with EtOAc and quenched with saturated aqueous sodium hydrogen carbonate solution, then the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% to 35% EtOAc / heptane to give the title compound (Compound C-5, 500 mg, 95% yield).

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.01 (s, 3 H) 0.04 (s, 3 H) 0.07 (s, 3 H) 0.11 (s, 3 H) 0.86-0.91 (m, 15 H) 0.93 (s, 9 H) 1.83 (dt, J = 14.9, 4.8 Hz, 1 H) 1.93 --2.00 (dt, J = 14.9, 4.8 Hz, 1 H) 2.19 --2.26 (m, 1 H) 2.29 (dd, dd, J = 14.9, 5.6 Hz, 1 H) 2.39 (dd, J = 16.6, 8.3 Hz, 1 H) 2.44 --2.66 (m, 4 H) 2.91 (dd, J = 9.5, 1.7 Hz, 1 H) 3.36 --3.41 (m, 1 H) 3.48 (td, J = 11.3, 2.7 Hz, 1 H) 3.59 (t, J = 7.1 Hz, 1 H) 3.74 --3.78 (m, 2 H) 3.80 (s, 3 H) 3.85 ( m, 1 H) 4.25 (d, J = 11.2 Hz, 1 H) 4.46 (d, J = 11.2 Hz, 1 H) 6.28 (d, J = 14.6 Hz, 1 H) 6.43 (dd, J = 14.6, 7.8 Hz, 1 H) 6.87 (d, J = 8.8 Hz, 2 H) 7.21 (d, J = 8.8 Hz, 2 H). ESI-MS (m / z): 813.30 [M + Na] ⁺
Example 14
((2R, 3R, 5S, 6S) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-((2S, 6S, 7S, E) -9-iodine-7-((4-4-) Methoxybenzyl) oxy) -6-methyl-4-oxonona-8-en-2-yl) tetrahydro-2H-pyran-2-yl) methyl4-methylbenzenesulfonate (Compound C-6)

Compound C-5: (2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl)) according to Example 13 under a nitrogen atmosphere. Oxy) -6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnona-8-ene-4-one (500 mg, In a 5 ° C. DCM (10 mL) solution of 0.63 mmol), pyridine (2.54 mL, 31.6 mmol), para-toluenesulfonyl chloride (723 mg, 3.79 mmol), and 4-dimethylaminopyridine (77 mg, 0. 63 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. Para-toluenesulfonyl chloride (150 mg, 0.79 mmol) was added to the reaction mixture at room temperature. The reaction mixture was then stirred at room temperature for 8 hours. The reaction mixture was diluted with DCM, quenched with saturated aqueous sodium hydrogen carbonate solution, and then the layers were separated. The aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% -25% EtOAc / heptane to give the title compound (Compound C-6, 560 mg, 94% yield).

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.01 (s, 3 H) 0.04 (s, 3 H) 0.04 (s, 3 H) 0.08 (s, 3 H) 0.81 (d, J = 6.8 Hz, 3 H) 0.83 (s, 9 H) 0.86 (d, J = 6.8 Hz, 3 H) 0.89 (s, 9 H) 1.81 (dt, J = 14.9, 4.5 Hz, 1 H) 1.91 --1.96 (m, 1) H) 2.15 --2.32 (m, 3 H) 2.36 --2.42 (m, 1 H) 2.43 (s, 3 H) 2.57 (d, J = 12.7 Hz, 1 H) 2.77 (dd, J = 16.6, 3.4 Hz, 1 H) 2.87 (dd, J = 9.0, 1.7 Hz, 1 H) 3.53 --3.58 (m, 2 H) 3.70 --3.75 (m, 1 H) 3.80 --3.85 (m, 1H) 3.81 (s, 3 H) 4.06 (dd, J = 10.0, 5.0 Hz, 1 H) 4.08 --4.16 (m, 1 H) 4.28 (d, J = 11.2 Hz, 1 H) 4.51 (d, J = 11.2 Hz, 1 H) 6.30 (d , J = 14.6 Hz, 1 H) 6.45 (dd, J = 14.6, 7.8 Hz, 1 H) 6.88 (d, J = 8.8 Hz, 2 H) 7.24 (d, J = 8.8 Hz, 2 H) 7.31 (d) , J = 8.3 Hz, 2 H) 7.76 (d, J = 8.3 Hz, 2 H).
Example 15
(2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -6- (azidomethyl) -3,5-bis ((tert-butyldimethylsilyl) oxy) tetrahydro-2H-pyran- 2-Il) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnona-8-en-4-one (Compound C-7)

Compound C-6: ((2R, 3R, 5S, 6S) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-((2S, 6S, 7S)) according to Example 14 under a nitrogen atmosphere. , E) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methyl-4-oxonona-8-en-2-yl) tetrahydro-2H-pyran-2-yl) methyl 4-methyl Sodium azide (385 mg, 5.92 mmol) was added to a solution of benzenesulfonate (560 mg, 0.59 mmol) in DMSO (5.6 mL) at 20 ° C. The reaction mixture was stirred at 85 ° C. After 2 hours, sodium azide (100 mg, 1.54 mmol) was added to the reaction mixture, then the reaction mixture was stirred at 85 ° C. for 14 hours. The reaction mixture was diluted with EtOAc and quenched with water, then the layers were separated. The organic extract was washed continuously with water and saturated brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue. The residue was subjected to silica gel flash column chromatography with 0% to 15% EtOAc / heptane to give the title compound (Compound C-7, 298 mg, 62% yield).

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.03 (s, 3 H) 0.06 (s, 3 H) 0.07 (s, 3 H) 0.10 (s, 3 H) 0.84 (d, J = 6.8 Hz, 3 H) 0.85 (d, J = 6.8 Hz, 3 H) 0.91 (s, 9 H) 0.92 (s, 9 H) 1.86 (dt, J = 15.0, 4.7 Hz, 1 H) 1.98 (dt, J = 15.0) , 2.9 Hz, 1 H) 2.19 --2.32 (m, 3 H) 2.41 --2.49 (m, 1 H) 2.58 (d, J = 12.7 Hz, 1 H) 2.94 (dd, J = 16.6, 2.9 Hz, 1 H) ) 2.98 (dd, J = 8.8, 2.0 Hz, 1 H) 3.02 (dd, J = 12.7, 2.9 Hz, 1 H) 3.47 (dt, J = 8.8, 2.7 Hz, 1 H) 3.49 --3.54 (m, 1) H) 3.63 (dd, J = 12.7, 8.8 Hz, 1 H) 3.69 --3.73 (m, 1 H) 3.81 (s, 3H) 3.83 --3.88 (m, 1 H) 4.26 (d, J = 11.7 Hz, 1 H) 4.50 (d, J = 11.7 Hz, 1 H) 6.26 (d, J = 14.6 Hz, 1 H) 6.42 (dd, J = 14.6, 7.8 Hz, 1 H) 6.87 (d, J = 8.8 Hz, 2) H) 7.22 (d, J = 8.8 Hz, 2 H).
Example 16
(((2R, 3R, 5S, 6S) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-((2S, 6S, 7S, E) -9-iodine-7-((4) -Methoxybenzyl) oxy) -6-methyl-4-oxonona-8-en-2-yl) tetrahydro-2H-pyran-2-yl) methyl) carbamate (Compound C-8)

Compound C-7: (2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -6- (azidomethyl) -3,5-bis ((tert-butyldimethyl)) according to Example 15. Cyril) oxy) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnona-8-en-4-one (298 mg, 0.37 mmol) Triphenylphosphine (1437 mg, 5.478 mmol) was added to a solution of THF (10 mL) and water (1.0 mL) at 20 ° C. The reaction mixture was stirred at 70 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a crude amine. In THF (10 mL) solution of 5 ° C. the crude amine obtained above _was Et 3 N (0.51mL, 3.66mmol) and di-diallyl carbonate (341 mg, 1.83 mmol) was added. The reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 0% -25% EtOAc / heptane to give the title compound (Compound C-8, 300 mg, 94% yield).

例１７
化合物Ｄ−４−１

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.05 --0.07 (m, 9 H) 0.11 (s, 3 H) 0.85 (d, J = 6.3 Hz, 3 H) 0.87 (d, J = 6.3 Hz, 3 H) 0.90 (s, 9 H) 0.93 (s, 9 H) 1.80 (dt, J = 15.0, 4.4 Hz, 1 H) 1.96 (dt, J = 15.0, 2.8 Hz, 1 H) 2.16 --2.29 (m) , 2 H) 2.32 --2.39 (m, 1 H) 2.53 --2.60 (m, 3 H) 2.86 (d, J = 7.3 Hz, 1 H) 3.04 --3.11 (m, 1 H) 3.30 --3.34 (m, 1) H) 3.38 --3.48 (m, 1 H) 3.58 (t, J = 7.1 Hz, 1 H) 3.70 --3.76 (m, 1 H) 3.80 (s, 3 H) 3.81 --3.81 (m, 1 H) 4.25 ( d, J = 11.2 Hz, 1 H) 4.46 (d, J = 11.2 Hz, 1 H) 4.53 --4.63 (m, 2 H) 5.19 (dd, J = 10.7, 1.5 Hz, 1 H) 5.32 (d, J = 17.1 Hz, 1 H) 5.47 (d, J = 6.8 Hz, 1 H) 5.88 --5.99 (m, 1 H) 6.28 (d, J = 14.6 Hz, 1 H) 6.43 (dd, J = 14.6, 7.8 Hz , 1 H) 6.87 (d, J = 8.8 Hz, 2 H) 7.21 (d, J = 8.8 Hz, 2 H). ESI-MS (m / z): 896.34 [M + Na] ⁺
Scheme D-1; Preparation of Compound D-7-1

Example 17
Compound D-4-1

Compound D-2: (S) -N- (2- (4-isopropyl-) obtained by the method described in Organic Letters (2002), 4 (25), 4431-4434 under a nitrogen atmosphere (in the glove box). 4,5-Dihydrooxazole-2-yl) -6-methoxyphenyl) methanesulfonamide (155 mg, 0.497 mmol) (CAS number; 546141-34-8), and 1,8-bis (dimethylamino) naphthalene (10,4-dihydrooxazole-2-yl) -6-methoxyphenyl). Chromium (II) chloride (55.5 mg, 0.452 mmol) was added to a 107 mg, 0.497 mmol) MeCN (0.75 mL) solution, and the resulting mixture was then stirred in a glove box at room temperature for 1 hour. did. The resulting green solution was subjected to compound C-8: allyl (((2R, 3R, 5S, 6S) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) -6-(((2R, 3R, 5S, 6S) -3,5-bis ((tert-butyldimethylsilyl) oxy) 2S, 6S, 7S, E) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methyl-4-oxonona-8-en-2-yl) tetrahydro-2H-pyran-2-yl ) Methyl) carbamate (99.0 mg, 0.113 mmol), compound D-1 (80.0 mg, 0) obtained by the method described in Journal of the American Chemical Society (1992), 114 (8), 3162-3164. .09 mmol) (CAS number; 157322-23-1), Journal of the American Chemical Society (2009), 131 (42), 15387-15393, compound D-3: dichloro (2,9). -Dimethyl-1,10-phenanthroline) Nickel (0.46 mg, 1.36 μmol) (CAS number; 21361-04-6) was added to a mixture of lithium chloride (3.83 mg, 0.09 mmol). The reaction mixture was then stirred in the glove box at room temperature for 60 minutes. The reaction mixture is then removed from the glove box and diluted with diethyl ether- EtOAc (5.0 mL-5.0 mL), followed by Floridil® (1600 mg, 15.94 mmol) (CAS Registry Number; 1343-88-0). Added to the mixture. The mixture was then stirred at room temperature for 30 minutes. The mixture was filtered (Celite®), washed with EtOAc / heptane = 2/1, and the filtrate was then concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 3% -55% EtOAc / heptane to give the title compound (Compound D-4-1, 140 mg, 95% yield).
Example 18
Compound D-5-1

Sodium hydrogen carbonate (28.8 mg, 0.34 mmol) and Dess-Martinpel in a 5 ° C. DCM (5.0 mL) solution of compound D-4 (140 mg, 0.09 mmol) according to Example 17 under a nitrogen atmosphere. Iodinan (72.7 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was diluted with DCM, quenched with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium sulfite solution, and then the layers were separated. The aqueous layer was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography with 2% -60% EtOAc / heptane to give the title compound (Compound D-5-1, 120 mg, 86%).

¹ H NMR (500 MHz, benzene-d6) δ ppm 0.01 -0.05 (m, 9 H) 0.10 --0.12 (m, 6 H) 0.15 (s, 3 H) 0.76 (d, J = 6.1 Hz, 3 H) 0.96 (s, 9 H) 1.02 (s, 9 H) 1.04 (s, 9 H) 0.95 --1.10 (m, 7H) 1.20 (d, J = 7.3 Hz, 3 H) 1.31 --1.37 (m, 3 H) 1.41 (dd, J = 12.8, 4.9 Hz, 1 H) 1.40 --1.58 (m, 4 H) 1.59 --1.164 (m, 1 H) 1.69 --1.89 (m, 3H) 1.90 --1.99 (m, 2 H) 2.02 ―― 2.25 (m, 8 H) 2.26 ―― 2.48 (m, 6 H) 2.49 ―― 2.70 (m, 6 H) 2.71 ―― 2.84 (m, 2 H) 3.00 ―― 3.07 (m, 1 H) 3.12 ―― 3.30 (m, 4 H) 3.36 (s, 3 H) 3.40 (br.s, 1 H) 3.44 --3.53 (m, 2 H) 3.65 (dd, J = 6.4, 4.0 Hz, 1 H) 3.69 --3.84 (m, 4H) 3.86 --4.03 (m, 4H) 4.07 ―― 4.17 (m, 3 H) 4.27 ―― 4.29 (m, 1H) 4.27 (d, J = 11.0 Hz, 1H) 4.48 --4.58 (m, 1 H) 4.49 (d, J) = 11.0 Hz, 1H) 4.65 --4.70 (m, 2 H) 4.68 (d, J = 5.5 Hz, 1H) 4.74- 4.86 (m, 2H) 4.78 (s, 1H) 4.93 (s, 1 H) 5.05 (d , J = 10.4 Hz, 1 H) 5.09 (br. S., 1 H) 5.19 (br. S., 1 H) 5.30 (dd, J = 17.1, 1.2 Hz, 1 H) 5.82 (d, J = 8.0 Hz, 1 H) 5.86 --5.96 (m, 1 H) 6.46 (d, J = 15.9 Hz, 1 H) 6.84 --6.92 (m, 3 H) 7.31 (d, J = 8.6 Hz, 2 H).
Example 19
Compound D-6-1

Imidazole hydrochloride (155 mg, 1.48 mmol) was dissolved in DMF (2.9 mL) to obtain a 0.5 M imidazole hydrochloride solution of DMF. 1.0 mL of this solution is mixed with 1.0 mL of TBAF (1.0 M, THF solution) to give a premixed solution of 0.5 M TBAF and 0.25 M imidazole hydrochloride in THF-DMF (1: 1). Obtained. In a nitrogen atmosphere, a solution of compound D-5-1 (80.0 mg, 0.05 mmol) according to Example 18 in DMF (7.0 mL) at 20 ° C. in THF-DMF (1: 1) prepared above. 0.588 mL of a premixed solution of TBAF (0.5 M) and imidazole hydrochloride (0.25 M) was added. The reaction mixture was stirred at room temperature for 14 hours. 1.6 g of calcium carbonate and 4.0 g of Dowex® 50 WX8 (hydrogen type, 200-400 mesh, SIGMA-ALDRICH) were added to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with EtOAc, then filtered (Celite®) and washed with EtOAc. The filtrate was concentrated under reduced pressure to give a crude residue. 1000 mg of calcium carbonate and 2.25 g of Dowex® 50WX8 were added to a solution of crude residue in EtOAc (6.0 mL). The mixture was stirred at room temperature for 2.5 hours. The mixture was then diluted with EtOAc, filtered (Celite®) and washed with EtOAc. The filtrate was concentrated under reduced pressure to give a crude residue (63.0 mg). The crude residue (63.0 mg) obtained above was added to a solution of DCM (6.0 mL), t-BuOH (0.6 mL) at room temperature and pH 7 phosphate buffer (0.6 mL, 1 / 15M). DDQ (111 mg, 0.49 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and then diluted with DCM to separate the layers. The aqueous layer was extracted with DCM (3 times). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to NH silica gel flash column chromatography with 10% to 100% EtOAc / heptane and then 10% MeOH / EtOAc to crudely purify the title compound (Compound D-6-1, 15.0 mg, 27%). Obtained.

¹ H NMR (500 MHz, methanol-d4) δ ppm 0.97 (d, J = 7.0 Hz, 3 H) 0.97 (d, J = 7.0 Hz, 3 H) 1.00 --1.02 (m, 1 H) 1.05 (d, J = 7.3 Hz, 3 H) 1.09 (d, J = 6.3 Hz, 3 H) 1.31 --1.45 (m, 6H) 1.46 --1.63 (m, 5H) 1.64 --1.75 (m, 3 H) 1.80 --1.86 (m) , 2 H) 1.87 --1.93 (m, 2 H) 1.94 --2.11 (m, 9H) 2.13 --2.27 (m, 8H) 2.33 (d, J = 2.4 Hz, 2 H) 2.39 (dd, J = 13.4, 6.1) Hz, 1 H) 2.44 (dd, J = 17.6, 2.0 Hz, 1 H) 2.55 (dd, J = 17.6, 9.3 Hz, 1 H) 2.75 --2.84 (m, 1 H) 2.97 (dd, J = 9.3, 2.0 Hz, 1 H) 3.21 (dd, J = 6.6, 4.6 Hz, 1 H) 3.32 (m, 1 H) 3.41 --3.46 (m, 1 H) 3.57 (br. S., 1 H) 3.60 (d, J = 11.7 Hz, 1 H) 3.67 --3.74 (m, 2 H) 3.78 (br. S., 1 H) 3.86 --3.90 (m, 2 H) 3.97 (d, J = 2.4 Hz, 1 H) 4.02- 4.11 (m, 4 H) 4.17 (dd, J = 6.6, 4.6 Hz, 1 H) 4.23 (dd, J = 11.5, 2.2 Hz, 1 H) 4.29 (br.s, 1 H) 4.31 (td, J = 9.3, 3.9 Hz, 1 H) 4.44 (d, J = 10.2 Hz, 1 H) 4.51 (d, J = 5.4 Hz, 2 H) 4.59 (t, J = 4.9 Hz, 1 H) 4.61 (dd, J = 7.3, 4.9 Hz, 1 H) 4.69 (t, J = 4.6 Hz, 1 H) 4.80 (s, 1 H) 4.85 --4.87 (m, 1 H) 5.01 (s, 1 H) 5.05 (s, 1 H) 5.16 (dd, J = 10.7, 1.0 Hz, 1 H) 5.28 (dd, J = 17.1, 2.0 Hz, 1 H) 5.92 (m, 1 H). ESI-MS (m / z): 1172.57 [M + Na] ⁺
Example 20
Compound D-7-1

Tetrakis (triphenylphosphine) in a room temperature DCM (2.0 mL) solution of compound D-6 (15.0 mg, 0.013 mmol) and pyrrolidine (10.8 μL, 0.13 mmol) according to Example 19 under a nitrogen atmosphere. ) Palladium (0) (7.53 mg, 6.52 μmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was subjected to NH silica gel flash column chromatography with 50% EtOAc / heptane and then 0% -20% MeOH / EtOAc to give a crude product. The obtained crudely purified product was purified by HPLC to obtain the title compound (D-7-1, 7.0 mg, 47%, retention time = 13.8 minutes).

HPLC conditions:
Column: YMC Pack Pro C18 (20mm x 250mm)
Detection wavelength: 200 nm
Column temperature: Room temperature Mobile phase: MeCN-water (0.05% AcOH)
Flow rate: 8 mL / min Eluate:
MeCN / water 25% (isocratic, 2 minutes), then MeCN / water 25% -60% (gradient, 20 minutes)

¹ H NMR (500 MHz, methanol-d4) δ ppm 0.99 (d, J = 6.7 Hz, 3 H) 1.00 --1.03 (m, 1 H) 1.04 (d, J = 7.3 Hz, 3 H) 1.06 (d, J = 7.3 Hz, 3 H) 1.10 (d, J = 6.1 Hz, 3 H) 1.29 --1.63 (m, 10 H) 1.65 --1.78 (m, 3 H) 1.79 --1.89 (m, 2 H) 1.92 --2.12 (m, 10 H) 1.93 (s, 3 H) 2.13 --2.36 (m, 9 H) 2.41 (dd, J = 13.5, 6.1 Hz, 1 H) 2.45 (dd, J = 17.6, 2.2 Hz, 1 H) 2.56 (dd, J = 17.6, 9.8 Hz, 1 H) 2.75 --2.84 (m, 1 H) 2.98 (dd, J = 9.8, 1.8 Hz, 1 H) 3.12 (dd, J = 12.8, 3.7 Hz, 1 H) ) 3.22 (dd, J = 6.4, 4.6 Hz, 1 H) 3.26 (dd, J = 13.2, 7.8 Hz, 1 H) 3.39 (d, J = 1.8 Hz, 1 H) 3.61 (d, J = 12.8 Hz, 1 H) 3.63 --3.68 (m, 2 H) 3.68 --3.76 (m, 2 H) 3.81 --3.94 (m, 3 H) 4.00 (d, J = 2.5 Hz, 1 H) 4.03 --4.15 (m, 4 H) ) 4.18 (dd, J = 6.4, 4.6 Hz, 1 H) 4.25 (ddd, J = 11.0, 4.3, 1.8 Hz, 1 H) 4.27 --4.36 (m, 2 H) 4.46 (d, J = 11.0 Hz, 1) H) 4.57 --4.65 (m, 2 H) 4.70 (t, J = 4.6 Hz, 1 H) 4.81 (d, J = 1.2 Hz, 1 H) 5.02 (br. S, 1 H) 5.06 (d, J = 1.8 Hz, 1 H). ESI-MS (m / z): 1066.96 [M + H] ⁺ , 1090.19 [M + Na] ⁺

Compound (1) (salt free form of compound D-7-1): ¹ H NMR (600 MHz, methanol-d4) δppm 0.98 (d, J = 7.2 Hz, 3 H) 1.00 (d, J = 6.8 Hz, 3 H) 1.02 (m, 1 H) 1.05 (d, J = 6.8 Hz, 3 H) 1.09 (d, J = 6.4 Hz, 3 H) 1.28 --1.45 (m, 5 H) 1.46 --1.59 (m, 4) H) 1.57 --1.63 (m, 1 H) 1.65 --1.71 (m, 1 H) 1.70 --1.75 (m, 2 H) 1.79 --1.86 (m, 2 H) 1.91 (dt, J = 14.9, 3.1 Hz, 1 H) 1.94 --2.11 (m, 8 H) 2.14 --2.34 (m, 9 H) 2.39 (dd, J = 13.2, 6.0 Hz, 1 H) 2.44 (dd, J = 17.4, 1.9 Hz, 1 H) 2.56 ( dd, J = 17.6, 9.6 Hz, 1 H) 2.69 (dd, J = 13.2, 4.2 Hz, 1 H) 2.79 (ddq, J = 15.9, 7.6, 2.0 Hz, 1 H) 2.92 (dd, J = 13.2, 8.3 Hz, 1 H) 2.97 (dd, J = 9.6, 1.7 Hz, 1 H) 3.21 (dd, J = 6.4, 4.9 Hz, 1 H) 3.29 (m, 1 H) 3.34 (dd, J = 8.3, 4.15 Hz, 1 H) 3.58 (br. S., 1 H) 3.60 (br.d, J = 11.3 Hz, 1 H) 3.68 --3.73 (m, 2 H) 3.80 (br. S., 1 H) 3.84- 3.90 (m, 2 H) 3.98 (d, J = 2.3 Hz, 1 H) 4.03 --4.13 (m, 4 H) 4.17 (dd, J = 6.4, 4.9 Hz, 1 H) 4.24 (ddd, J = 11.3, 4.5, 1.5 Hz, 1 H) 4.29 (dd, J = 4.0, 1.9 Hz, 1 H) 4.32 (td, J = 10.2, 4.2 Hz, 1 H) 4.44 (br. D, J = 11.0 Hz, 1 H) 4.59 (t, J = 4.5 Hz, 1 H) 4.62 ( dd, J = 7.4, 4.7 Hz, 1 H) 4.69 (t, J = 4.7 Hz, 1 H) 4.80 (br. S., 1 H) 4.87 (s, 1 H) 5.00 (br. S., 1 H) ) 5.05 (br.d, J = 1.1 Hz, 1 H)

ESI-MS (m / z): 1066.57 [M + H] ⁺ , 1088.55 [M + Na] ⁺

例２１
（Ｓ）−３−（（２Ｓ，３Ｓ，５Ｒ，６Ｒ）−３，５−ビス（（ｔｅｒｔ−ブチルジメチルシリル）オキシ）−６−（（（ｔｅｒｔ−ブチルジメチルシリル）オキシ）メチル）テトラヒドロ−２Ｈ−ピラン−２−イル）ブタナール（化合物Ａ−７）

標題化合物Ａ−７は、スキームＡに示されるとおり、Organic Letters (2009), 11(2), 409-412（CAS No;1095280-04-8）に記載の方法により、調製された化合物Ａ−１：（４ａＲ，５ａＳ，６Ｒ，８ａＳ，９ａＲ）−２，２−ジ−ｔｅｒｔ−ブチル−６−メチルヘキサヒドロフロ［２’，３’：５，６］ピラノ［３，２−ｄ］［１，３，２］ジオキサシリン−７（８ａＨ）−オンから得られた。 Synthesis scheme A of compound (D-6); preparation of compound A-7

Example 21
(S) -3-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro- 2H-pyran-2-yl) butanal (Compound A-7)

The title compound A-7 was prepared by the method described in Organic Letters (2009), 11 (2), 409-412 (CAS No; 1095280-04-8), as shown in Scheme A. 1: (4aR, 5aS, 6R, 8aS, 9aR) -2,2-di-tert-butyl-6-methylhexahydroflo [2', 3': 5,6] Pyrano [3,2-d] [ 1,3,2] Obtained from dioxacillin-7 (8aH) -one.

例２２
（（３Ｓ，４Ｒ）−５−ヨード−３−（（４−メトキシベンジル）オキシ）−４−メチルペンタ−１−イン−１−イル）トリメチルシラン（化合物Ｂ−３）

¹ H NMR (500 MHz, chloroform-d) ppm 0.00 (s, 3 H) 0.03 --0.08 (m, 12 H) 0.11 (s, 3 H) 0.88 (s, 9 H) 0.91 --0.92 (m, 21 H) 1.82 (dt, J = 15.0, 4.5 Hz, 1 H) 2.01 (dt, J = 15.0, 2.5 Hz, 1 H) 2.28 (ddd, J = 16.0, 7.3, 2.4 Hz, 1 H) 2.53 -2.58 (m, 1 H) 2.74 (ddd, J = 16.0, 5.5, 2.0 Hz, 1 H) 2.94 (dd, J = 9.0, 1.7 Hz, 1 H) 3.29 (td, J = 5.9, 2.0 Hz, 1 H) 3.68 (d , J = 5.9 Hz, 2 H) 3.75 --3.82 (m, 1 H) 3.82 --3.90 (m, 1 H) 9.73 (t, J = 2.4 Hz, 1 H)

Scheme B; Preparation of compound B-3

Example 22
((3S, 4R) -5-iodo-3-((4-methoxybenzyl) oxy) -4-methylpenta-1-in-1-yl) trimethylsilane (Compound B-3)

The title compound B-3 is compound B-1: (2S, 3S) prepared by the method described in WO 93/17690 A1 / US 5436238 A (CAS No; 157323-41-6) as shown in Scheme B. ) -3-((4-methoxybenzyl) oxy) -2-methyl-5- (trimethylsilyl) penta-4-in-1-ol.

例２３
（２Ｓ，６Ｓ，７Ｓ，Ｅ）−２−（（２Ｓ，３Ｓ，５Ｒ，６Ｒ）−３，５−ビス（（ｔｅｒｔ−ブチルジメチルシリル）オキシ）−６−（（（ｔｅｒｔ−ブチルジメチルシリル）オキシ）メチル）テトラヒドロ−２Ｈ−ピラン−２−イル）−９−ヨード−７−（（４−メトキシベンジル）オキシ）−６−メチルノン−８−エン−４−オン（化合物Ｃ−４）

^{1 1} H NMR (500 MHz, chloroform-d) δ ppm 0.21 (s, 9 H) 1.10 (d, J = 6.8 Hz, 3 H) 1.74 --1.84 (m, 1 H) 3.30 --3.37 (m, 2 H) 3.82 (s, 3 H) 3.96 (d, J = 7.3 Hz, 1 H) 4.44 (d, J = 11.2 Hz, 1 H) 4.73 (d, J = 11.2 Hz, 1 H) 6.89 (d, J = 8.8) Hz, 2 H) 7.30 (d, J = 8.8 Hz, 2 H).

Scheme C; Preparation of compound C-4

Example 23
(2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl)) Oxy) Methyl) Tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnon-8-en-4-one (Compound C-4)

The title compound C-4, as shown in Scheme C, follows the procedure for the preparation of compound C-8, compound A-7: (S) -3-((2S, 3S, 5R, 6R) -3, 5-Bis ((tert-butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) butanal and compound B-3: ((3S, 3S,) It was obtained from 4R) -5-iodo-3-((4-methoxybenzyl) oxy) -4-methylpenta-1-in-1-yl) trimethylsilane.

例２４
化合物Ｄ−４

¹ H NMR (500 MHz, chloroform-d) δ ppm 0.00 (s, 3 H) 0.03 --0.07 (m, 12 H) 0.10 (s, 3 H) 0.81 (d, J = 6.3 Hz, 3 H) 0.84 ( d, J = 6.3 Hz, 3 H) 0.89 (s, 9 H) 0.91 (s, 9 H) 0.92 (s, 9 H) 1.80 (dt, J = 15.0, 4.5 Hz, 1 H) 1.99 (dt, J) = 15.0, 2.5 Hz, 1 H) 2.17 (dd, J = 16.6, 10.2 Hz, 1 H) 2.20 --2.29 (m, 2 H) 2.43 --2.48 (m, 1 H) 2.54 (d, J = 12.7 Hz, 1 H) 2.87 (dd, J = 9.0, 1.7 Hz, 1 H) 2.99 (dd, J = 16.6, 2.9 Hz, 1 H) 3.27 (td, J = 5.8, 2.4 Hz, 1 H) 3.50 --3.56 (m) , 1 H) 3.66 --3.74 (m, 2H) 3.75 --3.78 (m, 1 H) 3.80 (s, 3 H) 3.81 --3.85 (m, 1 H) 4.26 (d, J = 11.7 Hz, 1 H) 4.50 (d, J = 11.7 Hz, 1 H) 6.26 (d, J = 14.6 Hz, 1 H) 6.42 (dd, J = 14.6, 7.8 Hz, 1 H) 6.87 (d, J = 8.3 Hz, 2 H) 7.21 (d, J = 8.3 Hz, 2 H). ESI-MS (m / z): 927.4 [M + Na] ⁺

Scheme D; Preparation of Compound D-6

Example 24
Compound D-4

Compounds obtained by the method described in Organic Letters (2002), 4 (25), 4431-4434 (CAS No; 546141-34-8) in MeCN (0.3 mL) under a nitrogen atmosphere (in the glove box). D-2: (S) -N- (2- (4-isopropyl-4,5-dihydrooxazole-2-yl) -6-methoxyphenyl) methanesulfonamide (29.1 mg, 0.093 mmol) and 1, To a solution of 8-bis (dimethylamino) naphthalene (20.0 mg, 0.093 mmol) is added chromium (II) chloride (10.4 mg, 0.085 mmol), followed by the resulting mixture at room temperature. Stirred in the glove box for 1 hour. The resulting solution is the compound C-4: (2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyl)) described in Example 23. Didimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6- Methylnone-8-en-4-one (18.4 mg, 0.02 mmol), compound D-1 (18.4 mg, 0.02 mmol), compound D-1 obtained by the method described in Journal of the American Chemical Society (1992), 114 (8), 3162-3164. Compound D-3: Dichloro obtained by the method described in 15.0 mg, 0.017 mmol) (CAS No; 157322-23-1), Journal of the American Chemical Society (2009) 131 (42) 1 5387-15393. Addition to premixture of (2,9-dimethyl-1,10-phenanthroline) nickel (0.09 mg, 0.254 μmol) (CAS No; 21361-04-6) and lithium chloride (1.0 mg, 0.024 mmol). did. The reaction mixture was stirred at room temperature for 60 minutes in a glove box. The reaction mixture was then removed from the glove box, diluted with diethyl ether (0.45 ml), and then Floridil® (300 mg, 2.99 mmol) (CAS No; 1343-88-0) was added to the mixture. The mixture was then stirred at room temperature for 30 minutes. The mixture was filtered (Celite®), washed with EtOAc / heptane = 1/1, and then the filtrate was concentrated under reduced pressure. Flash chromatography of the residue on silica gel with 3% -45% EtOAc / heptane gave the title compound (Compound D-4, 25.5 mg, 90% yield).

Example 25
Compound D-5

Under a nitrogen atmosphere, in a solution of compound D-4 according to Example 24 in DCM (1.5 mL) at 0 ° C., NaHCO ₃ (0.38 mg, 4.51 μmol) and Dess-Martin peryodinane (12.7 mg). , 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. Dess-Martin peryodinane (4.0 mg, 9.43 μmol) was added to the reaction mixture, then the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM and _{quenched with saturated aqueous NaHCO 3 and} aqueous saturated Na ₂ SO ₃ and then the layers were separated. The aqueous layer was extracted with DCM. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Flash chromatography of the residue on silica gel with 3% -40% EtOAc / heptane gave the title compound (Compound D-5, 20 mg, 80%).
¹ H NMR (500 MHz, chloroform-d) δ ppm -0.01 --0.01 (m, 6 H) 0.03 --0.08 (m, 15 H) 0.10 (s, 3 H) 0.80 (d, J = 6.3 Hz, 3 H) ) 0.84 (d, J = 6.8 Hz, 3 H) 0.87 (s, 9 H) 0.88 (s, 9 H) 0.91 (s, 9 H) 0.91 (s, 9 H) 0.94 --0.98 (m, 1H) 1.04 (d, J = 6.8 Hz, 3 H) 1.07 (d, J = 6.3 Hz, 3 H) 1.29 --1.51 (m, 5 H) 1.60 --1.68 (m, 3 H) 1.68 --1.77 (m, 2 H) 1.80 (dt, J = 14.8, 4.6 Hz, 1 H) 1.86 --2.03 (m, 7 H) 2.06 --2.27 (m, 9 H) 2.29 (d, J = 2.4 Hz, 2 H) 2.37 (dd, J = 16.3, 4.6 Hz, 1 H) 2.41 --2.50 (m, 1 H) 2.54 (d, J = 13.7 Hz, 1 H) 2.64 (dd, J = 16.6, 7.3 Hz, 1 H) 2.76 --2.90 (m, 3) H) 2.91 --3.04 (m, 3 H) 3.24 --3.30 (m, 1 H) 3.41 (dd, J = 5.6, 4.1 Hz, 1 H) 3.54 --3.59 (m, 1 H) 3.66 --3.75 (m, 3) H) 3.75 --3.78 (m, 1 H) 3.80 (s, 3 H) 3.81 --3.84 (m, 1 H) 3.86 -3.96 (m, 3 H) 4.03 --4.09 (m, 2 H) 4.20 (dd, J) = 6.8, 4.9 Hz, 1 H) 4.24 (d, J = 11.2 Hz, 1 H) 4.33 (br. S., 2 H) 4.39 -4.45 (m, 2 H) 4.47 (d, J = 11.7 Hz, 1 H) 4.57 (d, J = 7.3 Hz, 1 H) 4.60 (t, J = 4.4 Hz, 1 H) 4.69 (t, J = 4.6 Hz, 1 H) 4.75 (s, 1 H) 4.83 (s, 1) H) 5.00 (d, J = 13.2 H) z, 2 H) 6.23 (d, J = 16.1 Hz, 1 H) 6.66 (dd, J = 16.1, 6.8 Hz, 1 H) 6.87 (d, J = 8.8 Hz, 2 H) 7.21 (d, J = 8.8) Hz, 2 H).

Example 26
Compound D-6

1 ml TBAF (1.0 mmol, 1.0 M THF solution) was co-evaporated with toluene (3x1 mL). Imidazole hydrochloride (52 mg, 0.5 mmol) and DMF (2.0 mL) were added to the residue to obtain a premixed solution of 0.5 M TBAF and 0.25 M imidazole hydrochloride in DMF. Prepared above in a solution of compound D-5 (20.7 mg, 0.012 mmol) according to Example 25 of DMF (0.9 mL) and MeOAc (0.1 mL) under a nitrogen atmosphere at room temperature. A 0.241 mL premixed solution of TBAF (0.5 M) and imidazole hydrochloride (0.25 M) in DMF was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was added to 210 mg CaCO ₃ and 520 mg Dowex® 50WX8 (hydrogen form, 200-400 mesh, SIGMA-ALDRICH). The mixture was diluted with EtOAc (0.3 mL) and stirred at room temperature for 1 hour. The mixture was diluted with EtOAc (3 mL), then filtered through Celite® and washed with EtOAc. The filtrate was concentrated under reduced pressure to give a crude residue. The residue was added to EtOAc (3 mL). The solution was added to 210 mg CaCO ₃ and 520 mg Dowex® 50 WX8. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, filtered through Celite® and washed with EtOAc. The filtrate was concentrated under reduced pressure to give a crude residue (16.7 mg). In a solution of the crude residue (16.7 mg) obtained above in DCM (2.1 mL), t-BuOH (0.21 mL), and pH 7 phosphate buffer (0.21 mL, 1 / 15M) at room temperature. DDQ (28.3 mg, 0.125 mmol) was added. The reaction mixture was vigorously stirred at room temperature for 50 minutes. _{The reaction mixture was poured into saturated aqueous NaHCO 3} solution (8 mL) at room temperature with vigorous stirring, then diluted with DCM (10 mL) to separate the layers. The aqueous layer was extracted with DCM (2x5 mL). The combined organic extracts were _{dried over Na 2} SO ₄ , filtered and concentrated under reduced pressure. Flash chromatography of the residue on NH silica gel (FUJI SILYSIA CHEMICAL LTD, Chromatorex® NH silica gel) with 0% to 100% EtOAc / heptane and then 5% MeOH / EtOAc is a roughly purified title. The compound (4.9 mg) was given. The obtained product was purified by HPLC to give the title compound (Compound D-6, 2.2 mg, 16.5%). Holding time = 8.7 minutes.
HPLC conditions Column: YMC Pak Pro C18 (10 mm IDx250 mm)
Detection wavelength: 205 nm
Column temperature: Room temperature Mobile phase: MeCN-Water flow rate: 4.7 mL / min Eluate:
MeCN / water 60% (iso, 2 minutes), then MeCN / water 60% to 99% (gradient, 10 minutes), then MeCN / water 99% (iso, 11 minutes)

¹ H NMR (500 MHz, methanol-d4) δ ppm 0.97 (d, J = 6.8 Hz, 3 H) 0.99 (d, J = 7.3 Hz, 3 H) 1.00 --1.05 (m, 1 H) 1.05 (d, J = 7.3 Hz, 3 H) 1.09 (d, J = 6.8 Hz, 3 H) 1.30 --1.57 (m, 8 H) 1.57 --1.62 (m, 1 H) 1.64 --1.70 (m, 1 H) 1.70 --1.75 (m, 2 H) 1.78 --1.86 (m, 2 H) 1.90 (ddd, J = 14.8, 3.2, 3.2 Hz, 1 H) 1.94 --2.12 (m, 9H) 2.13 --2.25 (m, 4 H) 2.25- 2.34 (m, 5 H) 2.39 (dd, J = 13.2, 5.8 Hz, 1 H) 2.44 (dd, J = 17.4, 2.3 Hz, 1 H) 2.55 (dd, J = 17.6, 9.7 Hz, 1 H) 2.76 --2.83 (m, 1 H) 2.97 (dd, J = 9.7, 1.9 Hz, 1 H) 3.21 (dd, J = 6.6, 4.6 Hz, 1 H) 3.30 (m, 1 H) 3.41 (dd, J = 6.1 , 6.1 Hz, 1 H) 3.60 (d, J = 11.7 Hz, 1 H) 3.65 (d, J = 2.9 Hz, 1 H) 3.65 --3.68 (m, 2 H) 3.68 --3.74 (m, 2 H) 3.80 (br. S., 1 H) 3.84 --3.91 (m, 2 H) 3.98 (dd, J = 4.7, 2.2 Hz, 1 H) 4.03 --4.13 (m, 4 H) 4.17 (dd, J = 6.6, 4.6 Hz, 1 H) 4.23 (ddd, J = 11.6, 4.6, 2.0 Hz, 1 H) 4.28 --4.30 (m, 1 H) 4.32 (dd, J = 10.2, 4.2 Hz, 1 H) 4.44 (d, J = 11.2 Hz, 1 H) 4.59 (dd, J = 4.4, 4.4 Hz, 1 H) 4.61 (dd, J = 7.6, 4.8 Hz, 1 H) 4.69 (dd, J = 4.6, 4.6 Hz, 1 H) 4.80 ( d, J = 1.2 Hz, 1 H) 4.86 --4.87 (m, 1 H) 5.01 (br. S., 1 H) 5.06 (d, J = 1.5 Hz, 1 H). ESI-MS (m / z): 1089.5 [M + Na] ⁺

Synthesis of compound (E-2)
Example 27
Compound E-2

The title compound E-2 is the method described in WO 93/17690 A1 using the same procedures described for the preparation of compounds D-4, D-5 and D-6 (Examples 24, 25 and 26). Compound E-1 prepared by: (2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6- (((Tert-Butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnon-8-en-4- From all (CAS No; 157323-29-0) and compound D-1 (CAS No; 157322-23-1) prepared by the method described in the Journal of the American Chenical Society 1992, 114, 3162-3164. Obtained. Holding time = 14.7 minutes.
HPLC conditions Column: YMC Pak Pro C18 (4.6 mm IDx250 mm)
Detection wavelength: 200 nm
Column temperature: Room temperature Mobile phase: MeCN-Water flow rate: 1 ml / min Eluate:
MeCN / water 40% -98% (gradient, 20 minutes), then MeCN / water 98% (iso, 10 minutes)

スキームＧ；化合物Ｇ−４の調製

例２８
化合物Ｇ−４

¹ H NMR (600 MHz, methanol-d4) δ ppm 0.96 --0.98 (m, 6 H) 1.01 (d, J = 11.7 Hz, 1 H) 1.05 (d, J = 6.8 Hz, 3 H) 1.09 (d, J = 6.4 Hz, 3 H) 1.30 --1.56 (m, 7H) 1.63 --1.71 (m, 3H) 1.72 (d, J = 10.6 Hz, 1 H) 1.79-1.86 (m, 2H) 1.89 --2.12 (m, 3H) 11H) 2.13 --2.21 (m, 3 H) 2.22 --2.32 (m, 6H) 2.39 (dd, J = 13.2, 6.0 Hz, 1 H) 2.44 (dd, J = 17.8, 2.3 Hz, 1 H) 2.55 (dd) , J = 17.4, 9.4 Hz, 1 H) 2.79 (dd, J = 15.7, 5.5 Hz, 1 H) 2.97 (dd, J = 9.4, 1.5 Hz, 1 H) 3.21 (dd, J = 6.4, 4.9 Hz, 1 H) 3.28 (br. S., 2 H) 3.47 (br. S., 1 H) 3.51 (dd, J = 9.1, 3.8 Hz, 1 H) 3.60 (d, J = 11.7 Hz, 1 H) 3.66 --3.70 (m, 1 H) 3.67 --3.71 (m, 1 H) 3.68 --3.73 (m, 2 H) 3.78 (br. S., 1 H) 3.86 (br. S., 1 H) 3.86 --3.90 ( m, 1 H) 3.98 (q, J = 2.3 Hz, 1 H) 4.03 --4.08 (m, 1 H) 4.07 --4.10 (m, 1 H) 4.09 --4.12 (m, 1 H) 4.10 --4.12 (m, 1 H) 2 H) 4.17 (dd, J = 6.4, 4.9 Hz, 1 H) 4.23 (ddq, J = 11.0, 4.2, 1.9 Hz, 1 H) 4.29 (t, J = 1.9 Hz, 1 H) 4.32 (td, J) = 10.6, 4.5 Hz, 1 H) 4.44 (d, J = 11.0 Hz, 1 H) 4.59 (t, J = 4.3 Hz, 1 H) 4.62 (dd, J = 7.4, 4.7 Hz, 1 H) 4.69 (t) , J = 4.7 Hz, 1 H) 4.84 (br. S., 1 H) 4.87 (br. S., 1 H) 5.00 (br. S., 1 H) 5.05 (br. S., 1 H). ESI-MS (m / z): 1103.6 [M + Na] ⁺

Synthesis scheme F for compound (G-4); preparation of compound F-1

Scheme G; Preparation of compound G-4

Example 28
Compound G-4

The title compound G-4 is compound F-1: allyl-(2-((2R, 3R, 5S, 6S)-) (prepared by the procedure described in Scheme F) based on the procedure described in Scheme G. 3,5-bis ((tert-butyldimethylsilyl) oxy) -6-((2S, 6S, 7S, E) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methyl-4 -Oxonone-8-en-2-yl) tetrahydro-2H-pyran-2-yl) ethyl) carbamate, and the Journal of the American Chemical Society 1992, 114, 3162-3164 It was obtained as an acetate from compound D-1 (CAS No; 157322-23-1) prepared by the method described in. Holding time = 10.7 minutes.
HPLC conditions Column: YMC Pak Pro C18 (10 mm IDx250 mm)
Detection wavelength: 200 nm
Column temperature: Room temperature Mobile phase: MeCN-water (0.05% AcOH)
Flow velocity: 4.0 mL / min Eluate:
MeCN / water 25% (iso, 2 minutes), then MeCN / water 25% -60% (gradient, 20 minutes), then MeCN / water 60% (iso, 1 minute)

¹ H NMR (500 MHz, methanol-d4) δ ppm 0.99 (d, J = 6.7 Hz, 6 H) 1.00 --1.03 (m, 1 H) 1.06 (d, J = 6.7 Hz, 3 H) 1.10 (d, J = 6.1 Hz, 3 H) 1.26 --1.34 (m, 11 H) 1.65 --2.37 (m, 25 H) 2.40 (dd, J = 13.4, 6.1 Hz 1 H) 2.45 (dd, J = 17.1, 1.8 Hz, 1 H) 2.56 (dd, J = 17.7, 9.2 Hz, 1 H) 2.76 --2.84 (m, 1 H) 2.98 (dd, J = 9.8, 1.8 Hz, 1 H) 3.01 --3.17 (m, 2 H) 3.22 (dd, J = 6.7, 4.9 Hz, 1 H) 3.34 (dd, J = 6.1, 4.3 Hz, 1 H) 3.48 --3.53 (m, 2 H) 3.61 (d, J = 11.6 Hz 1 H) 3.69 --3.75 (m, 2 H) 3.82 (br. S., 1 H) 3.85 --3.92 (m, 2 H) 3.99 (br. S., 1 H) 4.04 --4.14 (m, 4 H) 4.18 (dd, J = 6.7, 4.2 Hz, 1 H) 4.25 (ddd, J = 11.6, 4.9, 1.8 Hz, 1 H) 4.29 --4.35 (m, 2 H) 4.46 (d, J = 11.0 Hz, 1 H) 4.58 --4.63 (m) , 2 H) 4.70 (t, J = 7.2, 4.6 Hz, 1 H) 4.81 (br. S., 1 H) 5.02 (br. S., 1 H) 5.06 (br. S., 1 H). ESI -MS (m / z): 1080.6 [M + H] ⁺ , 1102.6 [M + Na] ⁺ .

Synthesis of (H-2)
Example 29
Compound H-2

The title compound H-2 is compound F-1 prepared by the procedure described in Scheme F based on the procedure described in Scheme G: Allyl-2-((2R, 3R, 5S, 6S) -3,5. -Bis ((tert-butyldimethylsilyl) oxy) -6-((2S, 6S, 7S, E) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methyl-4-oxonon- 8-En-2-yl) tetrahydro-2H-pyran-2-yl) ethyl) carbamate, and the Journal of the American Chemical Society 2012, 134, 893-896 (the entire contents of which are incorporated herein by reference). ), It was obtained as an acetate from compound H-1 (CAS No; 1353268-98-0). Holding time = 10.2 minutes.
HPLC conditions Column: YMC Pak Pro C18 (10 mm IDx250 mm)
Detection wavelength: 200 nm
Column temperature: Room temperature Mobile phase: MeCN-water (0.05% AcOH)
Flow velocity: 4.0 ml / min Eluate:
MeCN / water 20% (iso, 2 minutes), then MeCN / water 20% -80% (gradient, 20 minutes)

例３０
化合物Ｉ−２

¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 0.99 (d, J = 7.0 Hz, 6 H) 1.02-1.04 (m, 1 H) 1.06 (d, J = 7.0 Hz, 3 H) 1.11 (d , J = 6.6 Hz, 3 H) 1.24 --1.45 (m, 7H) 1.46 --1.54 (m, 2 H) 1.54 --1.61 (m, 2 H) 1.62 --1.77 (m, 5 H) 1.78 --1.89 (m, 4 H) 1.90 --2.16 (m, 7 H) 2.16 --2.36 (m, 9 H) 2.39 (dd, J = 13.3, 5.9 Hz 2 H) 2.55 (dd, J = 19.9, 3.5 Hz, 1 H) 2.75- 2.85 (m, 1 H) 2.95 (dd, J = 9.8, 2.0 Hz, 1 H) 3.01 --3.17 (m, 2 H) 3.22 (dd, J = 6.4, 4.5 Hz, 2 H) 3.46 --3.53 (m, 1 H) 2 H) 3.61 (d, J = 10.5 Hz 1 H) 3.67 --3.76 (m, 2 H) 3.80 --3.84 (m, 1 H) 3.84 --3.92 (m, 2 H) 3.97 --4.01 (m, 1 H) 4.03 --4.14 (m, 3 H) 4.17 (dd, J = 4.1, 1.4 Hz, 1 H) 4.21 --4.27 (m, 1 H) 4.27 --4.34 (m, 2 H) 4.39 --4.43 (m, 1 H) 4.44 (d, J = 10.6 Hz, 1 H) 4.62 (dd, J = 7.2, 4.5 Hz, 1 H) 4.82 (br. S., 1 H) 4.88 (br. S., 1 H) 5.02 (br. s., 1 H) 5.06 (br. S., 1 H). ESI-MS (m / z): 1096.6 [M + H] ⁺ , 1118.6 [M + Na] ⁺ .

Synthesis scheme I of compound (I-2); preparation of compound I-1

Example 30
Compound I-2

The title compound I-2 was obtained by the method described in Scheme I, using the procedures described for the preparation of compounds D-4, D-5, and D-6 (Examples 24, 25, and 26). Compound I-1: (2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis ((tert-butyldimethylsilyl) oxy) -6- (2-methoxy) Ethyl) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl) oxy) -6-methylnon-8-en-4-one and compound D-1 (CAS No; 157322) Obtained from -23-1).

¹ H NMR (500 MHz, methanol-d4) δ ppm 0.98 (d, J = 6.8 Hz, 6 H) 1.00 --1.03 (m, 1 H) 1.06 (d, J = 6.8 Hz, 3 H) 1.10 (d, J = 5.8 Hz, 3 H) 1.29 --1.63 (m, 11 H) 1.65 --1.78 (m, 3 H) 1.78 2.13 (m, 12 H) 2.13 --2.36 (m, 9 H) 2.39 (dd, J = 14.1 , 5.4 Hz, 1 H) 2.45 (d, J = 17.1 Hz, 1 H) 2.57 (dd, J = 17.5, 9.7 Hz, 1 H) 2.76 --2.84 (m, 1 H) 2.98 (d, J = 10.2 Hz , 1 H) 3.19-3.24 (m, 1 H) 3.31-3.32 (m, 1 H) 3.32 (s, 3H) 3.49-3.57 (m, 4 H) 3.61 (d, J = 11.2 Hz, 1 H) 3.68 -3.76 (m, 2 H) 3.79 (br. S., 1 H) 3.84 --3.92 (m, 2 H) 3.98 (br. S., 1 H) 4.03 --4.15 (m, 4 H) 4.18 (t, t, J = 5.8 Hz, 1 H) 4.25 (d, J = 10.2 Hz, 1 H) 4.28 --4.36 (m, 2 H) 4.45 (d, J = 11.2 Hz, 1 H) 4.58-4.65 (m, 2 H) 4.70 (br. T, J = 5.4 Hz, 1 H) 4.81 (br. S., 1 H) 4.87 (br. S., 1 H) 5.02 (br. S., 1 H) 5.06 (br. S. , J = 1.5 Hz, 1 H). ESI-MS (m / z): 1117.6 [M + Na] ⁺ .

Synthesis of compound (J-1)
Example 31
Compound J-1

The title compound J-1 is compound E-1 :( 2S, 6S, 7S, E) -2-((2S, 3S, 5R, 6R) -3,5-bis) based on the procedure described in Scheme G. ((Tert-Butyldimethylsilyl) oxy) -6-(((tert-butyldimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-yl) -9-iodo-7-((4-methoxybenzyl)) It was obtained from oxy) -6-methylnon-8-ene-4-ol (CAS No; 157323-29-0) and compound H-1 (CAS No; 1353268-98-0). Holding time = 12.8 minutes.
HPLC conditions Column: YMC Pak Pro C18 (10 mm IDx250 mm)
Detection wavelength: 200 nm
Column temperature: Room temperature Mobile phase: MeCN-Water flow rate: 4.5 ml / min Eluate:
MeCN / water 35% (iso, 2 minutes), then MeCN / water 35% -99% (gradient, 20 minutes)

例３２
化合物Ｋ−２

¹ H NMR (500 MHz, methanol-d4) δ ppm 0.97 (d, J = 2.9 Hz, 3H) 0.99 (d, J = 2.9 Hz, 3 H) 1.00 --1.03 (m, 1 H) 1.05 (d, J) = 7.3 Hz, 3 H) 1.11 (d, J = 7.3 Hz, 3 H) 1.30 --1.44 (m, 6 H) 1.48 --1.57 (m, 4 H) 1.61 --1.76 (m, 4 H) 1.79 --1.87 ( m, 3 H) 1.91 --1.98 (m, 3 H) 2.00 --2.14 (m, 8 H) 2.24 --2.35 (m, 5 H) 2.37 --2.44 (m, 6 H) 2.55 (dd, J = 17.6, 9.8 Hz, 1 H) 2.68 --2.87 (m, 1 H) 2.94 (dd, J = 9.8, 2.0 Hz, 1 H) 3.22 (dd, J = 6.6, 4.7 Hz, 1 H) 3.22 (dd, J = 6.6, 4.7 Hz, 1 H) 3.26 --3.36 (m, 2 H) 3.42 --3.56 (m, 2H) 3.60 (d, J = 11.7 Hz, 1 H) 3.65 --3.75 (m, 3 H) 3.79 (br. S. , 1 H) 3.83 --3.93 (m, 2 H) 3.98 (d, J = 2.4 Hz, 1 H) 4.02 --4.36 (m, 3 H) 4.37 --4.51 (m, 2 H) 4.62 (dd, J = 7.6 , 4.6, Hz, 1 H) 4.82 (br. S., 1 H) 4.89 (br. S., 1 H) 5.01 (br. S., 1 H) 5.06 (br. S., 1 H). ESI -MS (m / z): 1119.6 [M + Na] ⁺ .

Synthesis of compound (K-2)
Scheme K; Preparation of compound K-1

Example 32
Compound K-2

The title compound K-2 is compound K-1: allyl ((2R, 4S) -2,4-bis ((tert-butyl)) prepared by the method described in Scheme K based on the procedure described in Scheme G. Dimethylsilyl) oxy) -4-((2S, 4S, 5S) -4-((tert-butyldimethylsilyl) oxy) -5-((2S, 6S, 7S, E) -9-iodo-7-( From (4-methoxybenzyl) oxy) -6-methyl-4-oxonon-8-en-2-yl) tetrahydrofuran-2-yl) butyl) carbamate and compound D-1 (CAS No; 157322-23-1) Obtained. Holding time = 9.5 minutes.
HPLC conditions Column: YMC Pak Pro C18 (10 mm IDx250 mm)
Detection wavelength: 200 nm
Column temperature: Room temperature Mobile phase: MeCN-water (0.05% AcOH)
Flow velocity: 4 ml / min Eluate:
MeCN / water 25% (iso, 2 minutes), then MeCN / water 25% -80% (gradient, 20 minutes)

例３３
化合物Ｌ−６

¹ H NMR (500 MHz, methanol-d ₄ ) δ ppm 0.96 (d, J = 6.8 Hz, 3 H) 1.01 (d, J = 7.3 Hz, 3 H) 1.00 --1.03 (m, 1 H) 1.05 (d) , J = 7.3 Hz, 3 H) 1.09 (d, J = 6.3 Hz, 3 H) 1.19 --1.63 (m, 9 H) 1.64 --1.76 (m, 4 H) 1.77 --1.89 (m, 3 H) 1.91- 2.21 (m, 11 H) 2.12-2.21 (m, 3 H) 2.22 --2.44 (m, 7 H) 2.44 (dd, J = 17.5, 1.9 Hz, 1 H) 2.55 (dd, J = 17.6, 9.3 Hz, 1 H) 2.75-2.87 (m, 2H) 2.97 (dd, J = 9.8, 2.0 Hz, 1 H) 3.05 (d, J = 11.7 Hz, 1 H) 3.21 (dd, J = 6.3, 4.4 Hz, 1 H) ) 3.58 (br. S., 1 H) 3.60 (d, J = 12.2 Hz, 1 H) 3.69 (br. S., 1 H) 3.73 (d, J = 10.2 Hz, 1 H) 3.77 (br. S ., 1 H) 3.84 --3.90 (m, 2 H) 3.98 --4.13 (m, 7 H) 4.17 (dd, J = 6.1, 4.6 Hz, 1 H) 4.24 (d, J = 11.2 Hz, 1 H) 4.29 (d, J = 3.9 Hz, 1 H) 4.32 (dd, J = 9.8, 3.9 Hz, 1 H) 4.45 (d, J = 10.2 Hz, 1 H) 4.58 --4.62 (m, 2 H) 4.69 (t, J = J = 4.6 Hz, 1 H) 4.80 (s, 1 H) 4.84 (s, 1 H) 5.02 (br. S., 1 H) 5.06 (br. S., 1 H). ESI-MS (m / z) ): 1110.6. [M + H] ⁺ , 1132.6 [M + Na] ⁺ .

Synthesis scheme L for compound (L-6); preparation of compound L-6

Example 33
Compound L-6

The title compound L-6 was prepared by the method described in Scheme L, according to the method described in the Journal of the American Chemical Society 2012, 134, 893-896, the entire contents of which are incorporated herein by reference. It was obtained as an acetate from the compound L-1 (CAS No; 1353269-09-6). Holding time = 5.6 minutes.
HPLC conditions Column: YMC Pak Pro C18 (10 mm IDx250 mm)
Detection wavelength: 205 nm
Column temperature: Room temperature Mobile phase: MeCN-water (0.05% AcOH)
Flow velocity: 4.7 mL / min Eluate:
MeCN / water 25% (iso, 2 minutes), then MeCN / water 25% -80% (gradient, 20 minutes), then MeCN / water 80% (iso, 2 minutes)

例３４
化合物Ｍ−３

¹ H NMR (500 MHz, methanol-d ₄ ) δ ppm 0.94 --1.03 (m, 7 H) 1.05 (d, J = 7.3 Hz, 3 H) 1.10 (d, J = 6.8 Hz, 3 H) 1.21 -2.41 (m, 36H) 2.44 (dd, J = 17.6, 2.2 Hz, 1 H) 2.54 (dd, J = 17.6, 9.2 Hz, 1 H) 2.75 --2.83 (m, 1H) 2.94 (dd, J = 9.5, 1.7 Hz, 1 H) 3.19 --3.23 (m, 1 H) 3.31 --3.33 (m, 1 H) 3.53 --3.73 (m, 7 H) 3.78 (br. S., 1 H) 3.84 --3.90 (m, 2 H) ) 3.97 --4.12 (m, 4 H) 4.16 (dd, J = 3.9, 1.0 Hz, 1 H) 4.21 (dd, J = 5.6, 3.2 Hz, 1 H) 4.21 --4.26 (m, 1 H) 4.26 --4.33 (m, 2 H) 4.38 --4.46 (m, 2 H) 4.58 --4.63 (m, 2 H) 4.81 (br. S., 1 H) 4.86 --4.87 (m, 1 H) 5.01 (br. S.,, 1 H) 5.06 (br. S., 1 H). ESI-MS (m / z): 1126.6 [M + H] ⁺ , 1148.6 [M + Na] ⁺ .

Synthesis scheme M for compound (M-3); preparation of compounds M-1 and M-2

Example 34
Compound M-3

The title compound M-3 is a compound prepared by the method described in Scheme M, using the procedures described for the preparation of compounds D-4, D-5, and D-6 (Examples 24, 25, and 26). M-1: (2S, 6S, 7S, E) -2-((2S, 3S, 5S) -3-((tert-butyldimethylsilyl) oxy) -5-((S) -2,2,3) , 3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl) tetrahydrofuran-2-yl) -9-iodo-7-((4-methoxybenzyl) ) Oxy) -6-methylnon-8-en-4-one and compound D-1 (CAS No; 157322-23-1).

¹ H NMR (500 MHz, methanol-d4) δ ppm 0.96 (d, J = 6.8 Hz, 3 H) 1.00 --1.03 (m, 1 H) 1.02 (d, J = 7.3 Hz, 3 H) 1.06 (d, J = 7.3 Hz, 3 H) 1.10 (d, J = 6.8 Hz, 3 H) 1.29 --1.63 (m, 10 H) 1.65 --1.78 (m, 5 H) 1.79 --1.89 (m, 3 H) 1.92 --2.12 (m, 7 H) 2.13 --2.36 (m, 10 H) 2.40 (dd, J = 13.4, 6.1 Hz, 1 H) 2.45 (dd, J = 17.5, 2.4 Hz, 1 H) 2.56 (dd, J = 18.0 , 9.7 Hz, 1 H) 2.76-2.84 (m, 1 H) 2.98 (dd, J = 9.7, 1.9 Hz, 1 H) 3.22 (dd, J = 6.3, 4.9 Hz, 1 H) 3.31-3.32 (m, 1 H) 1 H) 3.55 (m, 1H) 3.61 (d, J = 11.7 Hz, 1 H) 3.67-3.76 (m, 5 H) 3.84 --3.91 (m, 2 H) 3.95 (sept, J = 4.9 Hz, 1 H) 4.03 --4.11 (m, 4 H) 4.12 (dd, J = 6.6, 4.1 Hz, 1 H) 4.18 (dd, J = 6.3, 4.4 Hz, 1 H) 4.24 (ddd, J = 11.2, 9.0, 2.3 Hz, 1 H) 4.28 --4.31 (m, 1 H) 4.32 (dd, J = 10.2, 4.4 Hz, 1 H) 4.46 (d, J = 10.7 Hz, 1 H) 4.60 (t, J = 3.9 Hz, 1 H) 4.62 (dd, J = 7.3, 3.9 Hz, 1H) 4.70 (t, J = 4.4 Hz, 1 H) 4.81 (d, J = 1.5 Hz, 1 H) 4.87 (s, 1 H) 5.02 (br. S. , 1 H) 5.06 (d, J = 1.5 Hz, 1 H). ESI-MS (m / z): 1103.6 [M + Na] ⁺ .

Synthesis of compound (N-1)
Example 35
Compound N-1

The title compound N-1 was prepared by the procedure described in Scheme G and the method described in Scheme M. Compound M-2: Allyl-((S) -3-((tert-butyldimethylsilyl) oxy)-. 3-((2S, 4S, 5S) -4-((tert-butyldimethylsilyl) oxy) -5-((2S, 6S, 7S, E) -9-iodo-7-((4-methoxybenzyl)) Obtained as an acetate from oxy) -6-methyl-4-oxonone-8-en-2-yl) tetrahydrofuran-2-yl) propyl) carbamate and compound D-1 (CAS No; 157322-23-1). .. Holding time = 8.4 minutes.
HPLC conditions Column: YMC Pak Pro C18 (10 mm IDx250 mm)
Detection wavelength: 200 nm
Column temperature: Room temperature Mobile phase: MeCN-water (0.05% AcOH)
Flow velocity: 4.5 ml / min Eluate:
MeCN / water 25% (iso, 2 minutes), then MeCN / water 25% -80% (gradient, 20 minutes)

¹ H NMR (500 MHz, methanol-d ₄ ) δ ppm 0.97 (d, J = 6.8 Hz 3 H) 1.01 (m, 1H) 1.02 (d, J = 7.8 Hz 3 H) 1.07 (d, J = 7.3 Hz 3 H) 1.10 (d, J = 6.3 Hz, 3 H) 1.26 --1.41 (m, 6 H) 1.42 --1.56 (m, 4 H) 1.56 --1.64 (m, 2 H) 1.64 --1.78 (m, 4 H) ) 1.81 --1.88 (m, 3 H) 1.97 --2.11 (m, 7 H) 2.12 --2.22 (m, 2 H) 2.23 --2.37 (m, 9 H) 2.40 (dd, J = 13.2, 3.9 Hz, 1 H) ) 2.45 (dd, J = 17.1, 2.4 Hz, 1 H) 2.56 (dd, J = 17.8, 10.0 Hz 1 H) 2.75 --2.87 (m, 1 H) 2.98 (dd, J = 9.3, 1.9 Hz, 1 H) ) 3.06 --3.14 (m, 2H) 3.22 (dd, J = 5.8, 4.4 Hz, 1 H) 3.59 (br. S., 1 H) 3.61 (d, J = 11.2 Hz, 1 H) 3.68 --3.76 (m) , 3 H) 3.85 --3.92 (m, 2 H) 3.98 --4.03 (m, 1 H) 4.04 --4.14 (m, 4 H) 4.16 --4.20 (m, 1 H) 4.22 --4.28 (m, 1 H) 4.28 --4.35 (m, 2H) 4.46 (d, J = 11.21 Hz, 1 H) 4.58 --4.64 (m, 2 H) 4.70 (t, J = 4.9 Hz 1 H) 4.81 (br. S., 1 H) 4.87 (br. S., 1 H) 5.03 (br. S., 1 H) 5.07 (br. S., 1 H). ESI-MS (m / z): 1080.6 [M + H] ⁺ , 1102.6 [M + Na] ⁺ .

Pharmacological Test Examples General Information Natural halichondrin compounds and their modified compounds are known in the literature (eg, D. Uemura et al. "Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge" J. Am. Chem. Soc., 107, 4796 (1985); Marc Litaudon et al. "Antitumor Polyether Macrolides: New and Hemisynthetic Halichondrins from the New Zealand Deep-Water Sponge Lissodendoryx sp." J. Org. Chem., 1997, 62, 1868- See 1871). However, most of these are not readily available. For example, Dr. Uemura et al. Isolated 12.5 mg of halichondrin B, 35.0 mg of norhalichondrin A and 17.2 mg of homoharichondrin A from 600 kg of Halichondria okadai Kadota (eg, D. Uemura et al. "Norhalichondrin". A: An Antitumor Polyether Macrolide from a Marine Sponge "see J. Am. Chem. Soc., 107, 4796 (1985)). Among the native halichondrin compounds, halichondrin B shows the strongest antitumor activity against B-16 melanoma cells in vitro and is very active against L-1210 leukemia in vivo (eg, D). Uemura et al. "Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge" J. Am. Chem. Soc., 107, 4796 (1985)). Halichondrin C is also active in various in vivo models, but is unstable in aqueous solution as compared to halichondrin B. Norhalichondrin B is much weaker than Halichondrin B not only in vitro but also in vivo (eg, D. Uemura et al. "Norhalichondrin A: An Antitumor Polyether Macrolide from a Marine Sponge" J. Am. Chem. Soc., See 107, 4796 (1985)). In the following pharmacological tests, halichondrin B (Hali-B) is used as a control compound, if necessary.

Pharmacological test example 1. FaDu Growth Inhibition Assay In this assay, the growth inhibitory activity of the test compound in the human head and neck squamous cell line FaDu was measured. FaDu cells contain RPMI-1640 (Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum (FBS: Nichirei, 12D168) and penicillin / streptomycin in a 5% CO _{2 incubator (37 ° C.).} 187-02021) Cultured in medium. To each well of a 96-well plate (Becton Dickinson, 353219), 75 μL of ^{FaDu cell suspension adjusted to a concentration of 4 × 10 4} cells / mL in medium was added and the cells were placed in a 5% CO ₂ incubator (37). Incubated overnight at ° C.). The next day, 25 μL of compound (1) or halichondrin B in the 3-fold dilution series suspended in the medium was added to each well and _{cultured in a 5% CO 2} incubator (37 ° C.) for 3 days. Cell viability was then determined with the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) using an EnVision 2103 multi-label reader (PerkinElmer, Wellesley, MA). The value of the wells of cells to which the test compound was not added was defined as 100%, and the value of wells without cells was defined as 0%. The cell growth was calculated the concentration (IC ₅₀ value) of the test compound required to inhibit 50%, shown in Table 1.

Pharmacological test example 2. MDA-MB231 Growth Inhibition Assay In this assay, the growth inhibitory activity of the test compound in the human breast cancer cell line MDA-MB231 was measured. MDA-MB231 cells contain _{10% fetal bovine serum (FBS: Nichirei, 12D168) in a 5% CO 2} incubator (37 ° C.), penicillin / streptomycin in Dalbeco modified Eagle's medium (DMEM, Wako Pure Chemical Industries, Ltd., Wako Pure Chemical Industries, Ltd.). 044-29765) Cultured in medium. To each well of a 96-well plate (Becton Dickinson, 353219), 75 μL of ^{MDA-MB231 cell suspension adjusted to a concentration of 4 × 10 4} cells / mL in medium was added and the cells were placed in a 5% CO ₂ incubator. The cells were cultured overnight at (37 ° C.). The next day, 25 μL of compound (1) or halichondrin B in the 3-fold dilution series suspended in the medium was added to each well and _{cultured in a 5% CO 2} incubator (37 ° C.) for 3 days. Cell viability was then determined with the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) using an EnVision 2103 multi-label reader (PerkinElmer, Wellesley, MA). The value of the wells of cells to which the test compound was not added was defined as 100%, and the value of wells without cells was defined as 0%. The cell growth was calculated the concentration (IC ₅₀ value) of the test compound required to inhibit 50%, are shown in Table 2.

Pharmacological test example 3. HCC1954 Growth Inhibition Assay In this assay, the growth inhibitory activity of the test compound in the human breast cancer cell line HCC1954 was measured. HCC 1954 cells contain _{10% fetal bovine serum (FBS: Nichirei, 12D168), penicillin / streptomycin in a 5% CO 2} incubator (37 ° C.), 2 mM L-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 4500 mg / The cells were cultured in RPMI-1640 medium (ATCC30-2001) containing L glucose and 1500 mg / L sodium hydrogen carbonate. To each well of a 96-well plate (Becton Dickinson, 353219), 75 μL of ^{HCC1954 cell suspension adjusted to a concentration of 4 × 10 4} cells / mL in medium was added and the cells were placed in a 5% CO ₂ incubator (37). Incubated overnight at ° C.). The next day, 25 μL of compound (1) or halichondrin B in the 3-fold dilution series suspended in the medium was added to each well, and the resulting product was _{cultured in a 5% CO 2} incubator (37 ° C.) for 3 days. .. Cell viability was then determined with the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) using an EnVision 2103 multi-label reader (PerkinElmer, Wellesley, MA). The value of the wells of cells to which the test compound was not added was defined as 100%, and the value of wells without cells was defined as 0%. The cell growth was calculated the concentration (IC ₅₀ value) of the test compound required to inhibit 50%, shown in Table 3.

Pharmacological test example 4. Antitumor Effect in FaDu Subcutaneous Transplant Mouse Model as Single Agent Therapy Human head and neck squamous cell carcinoma (SCCHN) cell line FaDu cultured in RPMI-1640 medium containing 10% FBS, penicillin / streptomycin in a Hanks balanced salt solution. Te was adjusted to a concentration of 4.8 × 10 ⁷ cells / mL of cell suspension was prepared. The cell suspension was transplanted into the right ventral subcutaneous part of a 7-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Nine days after cell transplantation, the minor axis and major axis of each mouse tumor were measured using an electronic digital caliper (Digimatic ™ caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Tumor regression (%) = (1-minimum RTV) x 100

Based on the tumor volume obtained on the first day of administration, the mice were grouped so that the average value of the tumor volume was equal between the groups. Each test compound was dissolved in DMSO and the solution was frozen and stored until before use. Immediately prior to administration, the storage solution was diluted with saline containing 100 μM hydroxypropyl-β-cyclodextrin. Each evaluation sample was administered intravenously at a maximum tolerable dose (MTD). The experiment was carried out with 4 mice in one group. Tumor regression (%) of each test compound is shown in Table 4.

Pharmacological test example 5. Antitumor activity against OSC-19 in mouse subcutaneous transplant model as monotherapy The cells were cultured in Dalveco-modified Eagle's medium (DMEM) / Ham's F-12 (1: 1) medium containing 10% FBS, penicillin / streptomycin. human head and neck squamous cell carcinoma (SCCHN) cell line OSC-19, the cell suspensions were prepared and adjusted to a concentration of 1 × 10 ⁸ cells / ml in PBS, suspension Matrigel (TM) (BD Biosciences, # 366237) and 1: cell suspension concentration of 5 × 10 ⁷ cells / mL were mixed to prepare 1 ratio. The cell suspension was transplanted into the right ventral subcutaneous part of a 5-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Six days after the cell transplantation, the minor axis and major axis of the tumor of each mouse were measured using an electronic digital caliper (Digimatic ™ caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Tumor regression (%) = (1-minimum RTV) x 100

Based on the tumor volume obtained on the first day of administration, the mice were grouped so that the average value of the tumor volume was equal between the groups. The experiment was performed with 6 mice per group. The test compound was dissolved in physiological saline and administered intravenously at a dose of 0.06 mg / kg to 0.18 mg / kg once a week (Q7D × 2 schedule) for 2 weeks. Tumor regression (%) at each test dose is shown in Table 5.

Pharmacological test example 6. Antitumor activity 10% FBS for HCC1806 in a mouse subcutaneous transplantation model as monotherapy, the human breast cancer cell lines HCC1806 cultured in RPMI-1640 medium containing penicillin / streptomycin, of 1 × 10 ⁸ cells / mL in PBS cell suspensions were prepared and adjusted to a concentration, suspension Matrigel (TM) (BD Biosciences, # 366237) and 1: 1 ratio 5 × 10 ⁷ cells / mL of concentration of cells A suspension was prepared. The cell suspension was transplanted into the right ventral subcutaneous part of a 5-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Twelve days after cell transplantation, the minor axis and major axis of each mouse tumor were measured using an electronic digital caliper (Digimatic ™ caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Tumor regression (%) = (1-minimum RTV) x 100

Based on the tumor volume obtained on the first day of administration, the mice were grouped so that the average value of the tumor volume was equal between the groups. The experiment was performed with 6 mice per group. The test compound was dissolved in physiological saline and administered intravenously at 0.18 mg / kg once a week (Q7D × 2 schedule) for 2 weeks. The tumor regression (%) of compound (1) is shown in Table 6.

Pharmacological test example 7. Antitumor effect in FaDu subcutaneously transplanted mouse model in combination with cetuximab Human head and neck squamous cell carcinoma (SCCHN) cell line FaDu cultured in RPMI-1640 medium containing 10% FBS, penicillin / streptomycin in Hanks equilibrium salt solution. 5 × 10 ⁷ to adjust the concentration of cells / mL to prepare a cell suspension. The cell suspension was transplanted into the right ventral subcutaneous part of a 7-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Ten days after cell transplantation, the minor axis and major axis of each mouse tumor were measured using an electronic digital caliper (Digimatic ™ caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Tumor regression (%) on day 35 = (RTV on days 1-35) x 100

Based on the tumor volume obtained on the first day of administration, the mice were grouped so that the average value of the tumor volume was equal between the groups. Each test compound was dissolved in DMSO and the solution was stored frozen until before use. Immediately prior to administration, the storage solution was diluted with saline containing 100 μM hydroxypropyl-β-cyclodextrin. Each test compound was administered intravenously at doses of 1/4 MTD to 1 / 2MTD in combination with cetuximab (Erbitux, Merck Serono). The experiment was carried out with 4 mice in one group. The tumor regression (%) on day 35 of each test compound is shown in Table 7.

Pharmacological test example 8. Human HER-2 positive breast cancer cell line KPL-4 cultured in RPMI-1640 medium containing 10% FBS antitumor activity, penicillin / streptomycin in a KPL-4 subcutaneously transplanted mouse model combined with trastuzumab in a Hanks equilibrium salt solution. cell suspensions were prepared and adjusted to a concentration of 1 × 10 ⁸ cells / mL Te. The cell suspension was transplanted into the right ventral subcutaneous part of a 7-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. 16 days after cell transplantation, the minor axis and major axis of each mouse tumor were measured using an electronic digital caliper (Digimatic ™ caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Tumor regression (%) = (1-minimum RTV) x 100

Based on the tumor volume obtained on the first day of administration, the mice were grouped so that the average value of the tumor volume was equal between the groups. The experiment was performed with 6 mice per group. Each test compound was dissolved in DMSO and the solution was stored frozen until before use. Immediately before administration, the storage solution was diluted with saline. The test compound was administered intravenously at 0.09 mg / kg or 0.18 mg / kg in combination with trastuzumab (Herceptin, Genentech). Tumor regression for compound (1) is shown in Table 8.

Pharmacological test example 9. FaDu subcutaneous murine effect 10% for CD31 positive vessels in the model FBS, penicillin / a RPMI-1640 human head and neck squamous cell carcinoma (SCCHN) cultured in a medium cell line FaDu containing streptomycin, 5 × 10 ⁷ cells in PBS / Cell suspensions were prepared by adjusting the concentration to mL. The cell suspension was transplanted into the right ventral subcutaneous part of a 7-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Ten days after cell transplantation, the test compound in saline containing 100 μM hydroxypropyl-β-cyclodextrin was intravenously administered at a dose of 1/2 MTD to MTD. The experiment was performed with 3 mice in a group. Five days after administration, tumor samples were collected and fixed in IHC zinc fixative (BD Pharmingen) at 4 ° C. for 24 hours. The paraffin-embedded tissue was cut (3 μm), placed on a positively charged slide glass, and air-dried. Immunohistochemical staining of CD31 was performed using the Ventana autostainer model Discover XT (Roche Diagnostics) according to the manufacturer's protocol. The sections were deparaffinized, rehydrated, and antigen activated with CC1 (Ventana Medical Systems). Slides were blocked with blocker A and blocker B (endogenous biotin blocking kit, Roche Diagnostics). Sections were incubated with rat anti-mouse IgG CD31 antibody (Dianova) 2 μg / mL for 6 hours and then with 2.2 μg / mL biotinylated anti-rat IgG antibody (Jackson Immunoresearch Laboratories) for 32 minutes. Detection was performed with streptavidin-HRP D for 16 minutes and then _{incubated with DAB D and DAB H 2} O ₂ D (DABMap Kit, Ventana Medical Systems) for 8 minutes. Slides were counterstained with hematoxylin II (Roche Diagnostics) for 16 minutes and then incubated with brewing reagents for 4 minutes. Sections were dehydrated with stepwise ethanol, degreased by xylene exchange and covered with DPX (Merck).

Immunostained slides were scanned using the Vectra ™ 2 Automated Slide Imaging System (PerkinElmer). The number of blood vessels in the entire tumor was quantified by counting CD31 positive objects using inForm2 software (PerkinElmer). In addition, hematoxylin staining area was measured using inForm2 software (PerkinElmer) and used as the tumor area. The number of blood vessels was normalized by the area of the tumor area. The rate of increase in the number of blood vessels in the test compound-administered group was calculated by the following formula and is shown in Table 9.
Increase rate of blood vessel number (%) = ((number of blood vessels in test compound dosing group-number of blood vessels in control group) / number of blood vessels in control group) x 100

Pharmacological test example 10. FaDu subcutaneous effect 10% for alpha-SMA-positive CAF in the model FBS, penicillin / a RPMI-1640 human head and neck squamous cell carcinoma (SCCHN) cultured in a medium cell line FaDu containing streptomycin, 5 × 10 ⁷ cells in PBS Cell suspensions were prepared by adjusting the concentration to / mL. The cell suspension was transplanted into the right ventral subcutaneous part of a 5 to 6 week old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Charles River Japan Co., Ltd.) in a volume of 100 μL. Ten days after cell transplantation, the test compound in saline containing 100 μM hydroxypropyl-β-cyclodextrin was intravenously administered in 1/2 MTD and MTD. The experiment was performed with 3 mice in a group. Two days after administration, tumor samples were collected and fixed in IHC zinc fixative (BD Pharmingen) at 4 ° C. for 24 hours. The paraffin-embedded tissue was cut (3 μm), placed on a positively charged slide glass, and air-dried for 6 hours. Immunohistochemical staining of α-SMA was performed using the Ventana autostainer model Discover XT (Roche Diagnostics). The sections were deparaffinized, rehydrated, and antigen activated with proprietary buffer, EZPrep, and CC1 (Ventana Medical Systems). Sections were incubated with 5 μg / mL of mouse anti-α-SMA monoclonal antibody (clone 1A4, sigma) conjugated with alkaline phosphatase for 6 hours. Detection was performed with a RedMap kit (Ventana Medical Systems). Sections were dehydrated with stepwise ethanol, degreased by xylene exchange and covered with DPX (Merck). Successive tumor slices were deparaffinized and stained with Meyer hematoxylin (Muto Kagaku) for 1 minute. Sections were dehydrated with stepwise ethanol, degreased by xylene exchange and covered with DPX (Merck).

Immunostained slides were scanned using the Vectra ™ 2 Automated Slide Imaging System (PerkinElmer). The area of the α-SMA positive region in the entire tumor was quantified by counting α-SMA positive objects using inForm2 software (PerkinElmer). In addition, hematoxylin staining area was measured using inForm2 software (PerkinElmer) and used as the tumor area. The α-SMA positive region area was normalized by the tumor region area. The suppression rate of the α-SMA positive area of the test compound dosing group was calculated by the following formula and is shown in Table 10.

Pharmacological test example 11. HSC-2 orthotopic transplanted mouse model HSC-2-Luc cells into which the luciferase gene was introduced were established by gene transfer using a retrovirus. First, a DNA fragment encoding firefly luciferase was obtained from the pGL3-enhancer plasmid (GenBank #: U47297) and subcloned into the retroviral vector pCX4pur (GenBank #: AB086386). The retrovirus expression vector was then transfected into 293T cells (ATCC; Manassas, USA) with pGP and pE-Ampho plasmid (Takara Bio; Shiga, Japan) to generate a helper-free recombinant retrovirus. .. Next, HSC-2 cells were infected with recombinant retrovirus. Infected cells were selected from the polyclonal proliferative population by culturing for 2 weeks in the presence of puromycin (2 μg / mL).

Under anesthesia, the human SCCHN cell line, HSC-2-Luc, was transplanted into the tongue of female nude mice, 6-week-old (CAnN.Cg-Foxn1nu / CrlCrlj mice; Charles River; Shizuoka, Japan) (in 50 μL PBS). 1 x ¹⁰⁶ cells). Seven days after transplantation, tumor volume was analyzed using bioluminescent signals from HSC-2-Luc cells. For bioluminescence imaging, 0.1 mL of 15 mg / mL D-luciferin (Promega, Madison, WI) was injected intraperitoneally in nude mice under 1% to 2% inhaled isoflurane anesthesia. The bioluminescent signal was monitored using the IVIS SPECTRUM series (PerkinElmer, Waltham, MA) consisting of high-sensitivity cooling charge-coupled device cameras. Imaging data were grid-aligned using Living Image software (PerkinElmer, Waltham, MA) and the whole bioluminescent signal in each region of interest (ROI) was integrated. All bioluminescent images were acquired with 1 second exposure. Data were analyzed using the total number of photons emitted (photons / sec) in the ROI.

Based on the total number of photons released on the first day of administration, the mice were grouped so that the average value of the total number of released photons was equal between the groups. Compound (1) or cisplatin was administered intravenously over 3 weeks once weekly (Q7D x 3 schedule) with or without cetuximab (Erbitux, Merck Serono). Two experiments were performed using the same procedure and all data were collected from the experiments. Each group consisted of 16 mice.

Imaging data showed that only treatment with compound (1) with cetuximab clearly reduced bioluminescence signals in all mice after day 14 (FIGS. 6A-6B). Median time to live (MST) was calculated for each group of treatments as the median date of death. Life expectancy (Increase Life Span) (ILS) was calculated by the following formula: ILS (%) = (MST of animals treated with the test compound-MST of control animals) / MST of control animals × 100. The ILS (%) of each test compound is shown in Table 11.

Pharmacological test example 12. FaDu-Luc cells into which the luciferase gene was introduced were established by gene transfer using a FaDu subcutaneous transplantation model retrovirus combined with radiation. First, a DNA fragment encoding firefly luciferase was obtained from the pGL3-enhancer plasmid (GenBank #: U47297) and subcloned into the retroviral vector pCX4pur (GenBank #: AB086386). The retrovirus expression vector was then transfected into 293T cells (ATCC; Manassas, USA) with pGP and pE-Ampho plasmid (Takara Bio; Shiga, Japan) to generate a helper-free recombinant retrovirus. .. Next, FaDu cells were infected with the recombinant retrovirus. Infected cells were selected from the polyclonal proliferative population by culturing for 2 weeks in the presence of puromycin (2 μg / mL).

10% FBS, human SCCHN cell lines FaDu-Luc introduced luciferase gene were cultured in RPMI-1640 medium containing penicillin / streptomycin, and adjusted to a concentration of 5 × 10 ⁷ cells / mL in Hank's balanced salt solution Cell suspensions were prepared. The cell suspension was transplanted to the subcutaneous part of the right femur of a 6-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Thirteen days after cell transplantation, tumor volume was analyzed using bioluminescent signals from FaDu-Luc cells. For bioluminescence imaging, 0.1 mL of 15 mg / mL D-luciferin (Promega, Madison, WI) was injected intraperitoneally in nude mice under 1% to 2% inhaled isoflurane anesthesia. The bioluminescent signal was monitored using the IVIS SPECTRUM series (PerkinElmer, Waltham, MA) consisting of high-sensitivity cooling charge-coupled device cameras. Imaging data were grid-aligned using Living Image software (PerkinElmer, Waltham, MA) and the whole bioluminescent signal in each region of interest (ROI) was integrated. All bioluminescent images were acquired with 1 second exposure. Data were analyzed using the total number of photons emitted (photons / sec) in the ROI. The total number of emitted photons was calculated by the following formula:
Relative bioluminescence level = total number of photons released (day X) / total number of photons released (first day)
Tumor regression (%) = (1-minimum relative bioluminescence level) x 100

Based on the total number of photons released on the first day of administration, the mice were grouped so that the average value of the total number of released photons was equal between the groups. The experiment was performed with 6 mice per group. Compound (1) was administered by tail intravenous injection on the 1st and 8th days. Irradiation was performed at 18 Gy on the 4th and 11th days. Tumor regression for compound (1) is shown in Table 12.

Pharmacological test example 13. Mouse undifferentiated colon cancer cell line CT26 cultured in RPMI-1640 medium containing 10% FBS, penicillin / streptomycin, antitumor activity in a CT26 subcutaneously transplanted mouse model combined with an anti-mPD-1 antibody, in a Hanks balanced salt solution. cell suspensions were prepared and adjusted to a concentration of 2 × 10 ⁷ cells / mL. On day 1, the cell suspension was transplanted into the right ventral subcutaneous part of a 6-week-old BALB / c mouse (BALB / cAnNCrlCrlj, female, Charles River Laboratories, Inc.) in a volume of 100 μL. Two days after cell transplantation, mice were randomly divided into 4 groups. Each group consists of 8 mice. The minor axis and major axis of the tumor of each mouse were measured using an electronic digital caliper (Digimatic (trademark) caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
T / C = (mean tumor volume in the treatment group) / (mean tumor volume in the control group)
Inhibition of tumor growth (%) = (1-T / C) x 100

The test compound was administered intravenously at 0.09 mg / kg on days 3 and 11. Anti-mPD-1 antibody (BE0146, Bio X Cell) was intravenously administered at 10 mg / kg on days 3, 7, 11 and 15. The tumor growth inhibition (%) on day 15 of each test compound is shown in Table 13.

Pharmacological test example 14. Effect on tubulin polymerization in vitro (Fig. 10A)
The tubulin polymerization assay kit was purchased from Cytoskeleton (catalog number BK011P). The kit contained 1 bottle of lyophilized tubulin protein purified from porcine brain, 3 tubes of lyophilized GTP, 2 bottles of lyophilized assay buffer, and 1 bottle of tubulin glycerol buffer. The assay buffer was prepared by dissolving the contents in 10 mL of sterile deionized water. This solution was prepared with 80 mmol / L piperazine-N, N'-bis [2-ethanesulfonic acid] sesquiso sodium salt, 2.0 mmol / L magnesium chloride, 0.5 mmol / L ethylene glycol-bis (2-amino-ethyl ether). ) N, N, N', N'-tetra-acetic acid, pH 6.9, 10 μmol / L fluorescent reporter was contained. The buffer was stored at −70 ° C. until use. Tubulin glycerol buffer contains 80 mmol / L piperazine-N, N'-bis [2-ethanesulfonic acid] sesquiso sodium salt, 2.0 mmol / L magnesium chloride, 0.5 mmol / L ethylene glycol-bis (2-amino-). Ethylene ether) N, N, N', N'-tetra-acetic acid, 60% v / v glycerol, pH 6.9. This was stored at 4 ° C. until use. The GTP storage solution was prepared to a concentration of 100 mmol / L GTP by dissolving the contents of each tube in 100 μL of sterile deionized water. This solution was dispensed and stored at −70 ° C. until use. Tubulin storage solution (10 mg / mL) was prepared by adding 1.1 mL of a mixture of assay buffer and GTP storage solution (100: 1, v / v) to dissolve the tubulin powder. This solution was dispensed, frozen in liquid nitrogen, and then stored at −70 ° C. until use.

In the tubulin polymerization assay, a reaction mixture was prepared by mixing 820 μL of assay buffer, 17.6 μL of GTP storage solution, and 600 μL of tubulin glycerol buffer. The reaction mixture (1015 μL) was mixed with 240 μL of tubulin storage solution. This solution was called the tubulin reaction mixture and was used for testing and control well measurements. A tubulin-free reaction mixture was prepared by mixing 89.85 μL of the reaction mixture with 21.25 μL of assay buffer and blankwells were measured. Compound (1) solution (6.25-100 μmol / L; final concentration 0.625-10 μmol / L) or medium was added to the individual wells of a 96-well half-area microtiter plate in 5 μL. A tubulin reaction mixture or a tubulin-free reaction mixture was added to each well of the plate in 45 μL. Fluorescence emission at 460 nm (excitation wavelength at 360 nm) was measured every 2 minutes for 90 minutes using a SpectraMax® M5e microplate reader (molecular device). Fluorescence enhancement occurs after tubulin polymerization because the fluorescence reporter is incorporated into the microtubes by tubulin polymerization. The assay was performed with a two-point measurement. The assay demonstrated that compound (1) inhibits tubulin polymerization in a concentration-dependent manner. The fluorescence intensity at each time point was calculated by the following formula:
Fluorescence intensity = average fluorescence measurement of test well or control well-average fluorescence measurement of blank well; blank well: contains tubulin-free medium; control well: contains medium and tubulin; test well: compound and tube Contains phosphorus.

Pharmacological test example 15. Cell-based microtubule dynamics assay (Fig. 10B)
Microtubule kinetics assays in cells were performed using a U2OS-EB3-AG osteosarcoma cell line that stably expresses a fusion protein of EB3 (microtubule plus end binding protein) and Azami-Green (EB3-AG). U2OS-EB3-AG cells were cultured in humidified 5% CO ₂ , 37 ° C., RPMI-1640 medium containing 10% FBS, penicillin-streptomycin. Microtubule dynamics in living cells can be visualized as the movement of the comet-like structure of EB3-AG. U2OS-EB3-AG cells on a glass-based culture plate (EZVIEW plate, AGC technoglass, Japan) were treated with compound (1) at the concentration shown in the figure and treated with a 60x oil immersion objective lens (BZ-X710). , Keyence, Japan), microtubule dynamics were monitored by time-lapse imaging using a fluorescence microscope. Still images at each time point are presented in FIG. 10B. The high-magnification image of the part surrounded by the square is shown in the inset. When compound (1) was treated with 0.5 nM (50% growth inhibitory concentration in U2OS-EB3-AG cells), the comet-like structure became difficult to observe about 60 minutes after compound was added. These results clearly demonstrated that compound (1) has the ability to suppress microtubule dynamics.

Pharmacological test example 16. In vitro growth inhibitory activity (Fig. 11)
In vitro growth inhibition assays for compound (1) included human esophageal squamous cell carcinoma (OE21, TE-8), human esophageal sarcoma (OE33), human uterine sarcoma (MES-SA, MES-SA-Dx5-Rx1). This was done using a small panel of cancer cell lines. All cell lines were cultured in 5% CO ₂ incubator (37 ° C.) in RPMI-1640 medium containing 10% FBS, penicillin-streptomycin. To each well of a 96-well plate (Becton Dickinson, 353219) was added 75 μL of cell suspension adjusted to a concentration of ^{4 × 10 4} _{cells / mL in medium and the cells were placed in a 5% CO 2} incubator (37 ° C.). ) Was incubated overnight. The next day, 25 μL of compound (1) in the 3-fold dilution series suspended in medium was added to each well and _{incubated in a 5% CO 2} incubator (37 ° C.) for 72 hours. Cell viability was then determined by the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) using a 2013 EnVision® multi-label reader (PerkinElmer, Wellesley, MA). The value of the wells of cells to which the test compound was not added was defined as 100%, and the value of wells without cells was defined as 0%. Having calculated the concentration _{(IC 50} value) of the compound required to inhibit cell growth by 50% (1) shown in FIG. 11. The P-gp sensitivity was calculated as the ratio between _{an IC 50} value in _{an IC 50} value and MES-SA cells in MES-SA-Dx5-Rx1 cells overexpressing P-gp.

Pharmacological test example 17. Antitumor effect in KPL-4 transplanted mouse model as monotherapy; antitumor effect in mouse COLO-704 transplanted model as monotherapy (Fig. 12)
10% FBS, penicillin - adjusts the human HER-2 positive breast cancer cell line KPL-4 cultured, the concentration of 1 × 10 ⁸ cells / mL in Hank's balanced salt solution in Dulbecco's modified Eagle's medium containing streptomycin (DMEM) To prepare a cell suspension. The cell suspension was transplanted into the right ventral subcutaneous part of an 8-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Charles River Japan Co., Ltd.) in a volume of 100 μL. 11 days after cell transplantation (1st day), the minor axis and major axis of the tumor of each mouse were measured using an electronic digital caliper (Digimatic (trademark) caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula. did:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Weight ratio (RBW) = body weight (day X) / body weight (day 1)

Based on the tumor volume obtained on the first day, the mice were grouped so that the average value of the tumor volume was equal between the groups. The experiment was performed with 6 mice per group. The test compound was dissolved in DMSO and the solution was stored frozen until before use. Immediately before administration, the storage solution was diluted with saline. The test compound in saline was intravenously administered once weekly at 20 μg / kg, 60 μg / kg, or 180 μg / kg for 2 weeks (1st and 8th day). Tumor regression was observed in the 60 μg / kg and 180 μg / kg treatment groups, and administration at 180 μg / kg completely eradicated the transplanted tumor in all mice on day 15.

10% FBS, penicillin - Human ovarian cancer cell line COLO-704 was cultured in RPMI-1640 containing streptomycin, and adjusted to a concentration of 1 × 10 ⁸ cells / mL in Hank's balanced salt solution cell suspension Was prepared. The cell suspension was transplanted into the right ventral subcutaneous part of a 5-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Nine days after cell transplantation (day 1), the minor axis and major axis of each mouse tumor were measured using an electronic digital caliper (Digimatic (trademark) caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated using the following formula. did:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Weight ratio (RBW) = body weight (day X) / body weight (day 1)

Based on the tumor volume obtained on the first day, the mice were grouped so that the average value of the tumor volume was equal between the groups. The experiment was performed with 6 mice per group. The test compound was dissolved in DMSO and the solution was stored frozen until before use. Immediately before administration, the storage solution was diluted with saline. The test compound in saline was intravenously administered once weekly at 20 μg / kg, 60 μg / kg, or 180 μg / kg for 2 weeks (1st and 8th day). Treatment with the compound induced tumor regression at 180 μg / kg and delayed tumor growth at 60 μg / kg. Administration at 180 μg / kg completely eradicated the transplanted tumor in all mice on day 22.

Pharmacological test example 18. Effect on CD31-positive blood vessels in FaDu subcutaneously transplanted mouse model (Fig. 13)
10% FBS, penicillin - a RPMI-1640 human head and neck squamous cell carcinoma (SCCHN) cultured in a medium cell line FaDu containing streptomycin, and adjusted to a concentration of 5 × 10 ⁷ cells / mL in a medium cell suspension The solution was prepared. The cell suspension was transplanted into the right ventral subcutaneous part of a 6-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Mice were grouped so that the average tumor volume was equal between the groups 10 days after cell transplantation. The experiment was performed with 6 mice per group. Each test compound was dissolved in DMSO and the solution was frozen and stored until before use. Immediately before administration, the storage solution was diluted with saline. The test compound in saline was administered intravenously at 20 μg / kg, 60 μg / kg, or 180 μg / kg. Five days after the single dose, tumor samples were collected and fixed in IHC zinc fixative (BD Pharmingen) at 4 ° C. for 24 hours. The paraffin-embedded tissue was cut (3 μm), placed on a positively charged slide glass, and air-dried. Immunohistochemical staining of CD31 was performed using the Ventana autostainer model Discover XT (Roche Diagnostics) according to the manufacturer's protocol. The sections were deparaffinized, rehydrated, and antigen activated with CC1 (Ventana Medical Systems). Slides were blocked with blocker A and blocker B (endogenous biotin blocking kit, Roche Diagnostics). Sections were incubated with rat anti-mouse IgG CD31 antibody (dianova) 2 μg / mL for 6 hours and then with 2.2 μg / mL biotinylated anti-rat IgG antibody (Jackson Immunoresearch Laboratories) for 32 minutes. Detection was performed with streptavidin-HRPD for 16 minutes and then _{incubated with DAB D and DAB H 2} O ₂ D (DABMap Kit, Ventana Medical Systems) for 8 minutes. Slides were counterstained with hematoxylin II (Roche Diagnostics) for 16 minutes and then incubated with brewing reagents for 4 minutes. Sections were dehydrated with stepwise ethanol, degreased by xylene exchange and covered with DPX®®. Immunostained slides were scanned using the Vectra® 2 Automated Slide Imaging System (PerkinElmer). The number of blood vessels in the entire tumor was quantified by counting CD31 positive objects using inForm2 software (PerkinElmer). In addition, hematoxylin staining area was measured using inForm2 software (PerkinElmer) and used as the tumor area. The number of blood vessels was normalized by the area of the tumor area. A single dose of the test compound at doses of 20, 60, 180 μg / kg increased the number of tumor vessels. The ratio of the number of blood vessels in the test compound-administered group compared to the untreated group was calculated by the following formula:
Tumor blood vessel ratio = number of blood vessels in the test compound-administered group / number of blood vessels in the untreated group

Pharmacological test example 19. Effect on α-SMA positive CAF in FaDu subcutaneously transplanted mouse model (Fig. 14)
10% FBS, penicillin - a RPMI-1640 human head and neck squamous cell carcinoma (SCCHN) cultured in a medium cell line FaDu containing streptomycin, and adjusted to a concentration of 5 × 10 ⁷ cells / mL in a medium cell suspension The solution was prepared. The cell suspension was transplanted into the right ventral subcutaneous part of a 6-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Mice were grouped so that the average tumor volume was equal between the groups 10 days after cell transplantation. The experiment was performed with 5 mice per group. Each test compound was dissolved in DMSO and the solution was frozen and stored until before use. Immediately before administration, the storage solution was diluted with saline. The test compound in physiological saline was intravenously administered at 20 μg / kg, 60 μg / kg, or 180 μg / kg. Tumor samples were collected 2 or 5 days after the single dose and fixed in IHC zinc fixative (BD Pharmingen) at 4 ° C. for 24 hours. The paraffin-embedded tissue was cut (3 μm), placed on a positively charged slide glass, and air-dried. The sections were deparaffinized and rehydrated, and antigen activation was performed using microwaves with 1 mM EDTA at pH 6.0. Sections were blocked with 1% BSA in TBS. Sections were incubated with 5 μg / mL of mouse anti-α-SMA monoclonal antibody (clone 1A4, sigma) conjugated with alkaline phosphatase for 2.5 hours. Detection was performed with the First Red II Substrate Kit (Nichirei Bioscience). Sections were counterstained with Meyer hematoxylin (Muto Kagaku) for 50 seconds. Sections were dehydrated with stepwise ethanol, degreased by xylene exchange and covered with DPX (Merck). Immunostained slides were scanned using the Vectra® 2 Automated Slide Imaging System (PerkinElmer). The area of the α-SMA positive region in the entire tumor was quantified by counting α-SMA positive objects using inForm2 software (PerkinElmer). In addition, hematoxylin staining area was measured using inForm2 software (PerkinElmer) and used as the tumor area. The α-SMA positive region area was normalized by the tumor region area. A single dose of the test compound significantly reduced the α-SMA positive area at doses of 60 and 180 μg / kg on day 3 and at doses of 180 μg / kg on day 6. The suppression rate of the α-SMA positive area of the test compound dosing group was calculated by the following formula:
α-SMA ratio = α-SMA area of test compound dosing group / α-SMA area of untreated group

Pharmacological test example 20. Effect on Tenascin-C and EDA-fibronectin in a FaDu subcutaneously transplanted mouse model (Fig. 15)
10% FBS, penicillin - a RPMI-1640 human head and neck squamous cell carcinoma (SCCHN) cultured in a medium cell line FaDu containing streptomycin, and adjusted to a concentration of 5 × 10 ⁷ cells / mL in a medium cell suspension The solution was prepared. The cell suspension was transplanted into the right ventral subcutaneous part of a 6-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Mice were grouped so that the average tumor volume was equal between the groups 10 days after cell transplantation. The experiment was performed with 5 mice per group. Compound (1) was dissolved in DMSO and the solution was frozen and stored until before use. Compound (1) (180 μg / kg) and cetuximab (CTX, Erbitux®, Merck Serono) (10 mg / kg) were diluted with saline on day 1 and intravenously injected. Five days after the single dose, tumor samples were collected and fixed in IHC zinc fixative (BD Pharmingen) at 4 ° C. for 24 hours. The paraffin-embedded tissue was cut (3 μm), placed on a positively charged slide glass, and air-dried. The sections were deparaffinized and rehydrated, and for tenascin-C, the antigen activated with 1 mM EDTA at pH 6.0 was recovered using microwaves. No antigen-activated antigen recovery procedure was required for EDA-fibronectin. Sections were incubated with BLOXALL blocking solution (Vector Laboratories) for 10 minutes, mouse-on-mouse Ig blocking reagent (Vector Laboratories) for 1 hour, and then with 2.5% normal horse serum for 30 minutes to block endogenous peroxidase. For immunohistochemical staining of tenascin-C, sections were incubated overnight at 4 ° C. with 5 μg / mL of mouse anti-tenascin-C monoclonal antibody (clone 4C8MS, IBL). For immunohistochemical staining of EDA-fibronectin, sections were incubated with 1.5 μg / mL of mouse anti-EDA-fibronectin monoclonal antibody (clone IST-9, Abcam) for 1 hour at room temperature. Detection was performed with a mouse-on-mouse ImmPRESS ™ peroxidase polymer kit (Vector Laboratories). Sections were counterstained with Meyer hematoxylin (Muto Kagaku) for 50 seconds. Sections were dehydrated with stepwise ethanol, degreased by xylene exchange and covered with DPX (Merck). Immunostained slides were scanned using the Vectra ™ 2 Automated Slide Imaging System (PerkinElmer). Expression levels of both tenascin-C and EDA-fibronectin were reduced in tumors treated with compound (1) and CTX compared to control tumors.

Pharmacological test example 21. Antitumor effect in FaDu subcutaneously transplanted mouse model in combination with cetuximab (Fig. 16)
10% FBS, penicillin - a RPMI-1640 human head and neck squamous cell carcinoma cultured in a medium (SCCHN) cell line FaDu containing streptomycin, and adjusted to a concentration of 5 × 10 ⁷ cells / mL in Hank's balanced salt solution Cell suspensions were prepared. The cell suspension was transplanted to the right ventral subcutaneous part of a thymus-deficient mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, 7 weeks old, Charles River Japan) in a volume of 100 μL. Ten days after cell transplantation (day 1), the length and width of the tumor in each mouse were measured using an electronic digital caliper (Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)

Mice were randomly grouped based on TV (day 1). Each group consisted of 6 mice. Compound (1) was dissolved in DMSO and the solution was frozen and stored until before use. Compound (1) (20, 60, or 180 μg / kg) and cetuximab (CTX, Erbitux®, Merck Serono) (10 mg / kg) were diluted with saline and intravenously injected on day 1. .. The changes in RTV of each group are shown in FIG. At the doses of 180 μg / kg and 60 μg / kg, the antitumor efficacy of compound (1) in combination with CTX was stronger than that of CTX monotherapy, and there was tumor regression. The antitumor efficacy of compound (1) at a dose of 20 μg / kg in combination with CTX tended to be stronger than the antitumor efficacy of CTX monotherapy.

Pharmacological test example 22. Antitumor effect in a mouse model of soft tissue sarcoma transplantation as monotherapy (Fig. 17)
MES-SA
10% FBS, penicillin - human uterine sarcoma cell line MES-SA cultured in RPMI-1640 containing streptomycin, the cell suspension was adjusted to a concentration of 2 × 10 ⁸ cells / mL in Hank's balanced salt solution prepared, suspension Geltrex (TM) (thermo Fisher Scientific, # A1413202) and 1: to prepare a cell suspension at a concentration of 1 × 10 ⁸ cells / mL were mixed in a ratio. The cell suspension was transplanted into the right ventral subcutaneous part of a 6-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Six days after cell transplantation (day 1), the minor axis and major axis of each mouse tumor were measured using an electronic digital caliper (Digimatic (trademark) caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated using the following formula. did:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)

Based on the tumor volume obtained on the first day, the mice were grouped so that the average value of the tumor volume was equal between the groups. The experiment was performed with 6 mice per group. The test compound was dissolved in DMSO and the solution was cryopreserved before use. Immediately before administration, the storage solution was diluted with saline. The test compound in saline was intravenously administered once weekly at 180 μg / kg for 2 weeks (1st and 8th day). Antitumor activity was observed in the treated group with delayed tumor growth.

HT-1080
10% FBS, NEAA, the human fibrosarcoma cell line HT-1080 was cultured in E-MEM containing antibiotics, was adjusted a concentration of 3 × 10 ⁷ cells / mL in a medium to prepare a cell suspension .. The cell suspension was transplanted into the right ventral subcutaneous part of a thymus-deficient mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, 6 weeks old, Charles River Japan) in a volume of 100 μL. Six days after cell transplantation (day 1), the length and width of the tumor in each mouse were measured using an electronic digital caliper (Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)

Mice were randomly grouped based on TV (day 1). Each group consisted of 6 mice. Compound (1) was dissolved in DMSO and the solution was cryopreserved until before use. Compound (1) (180 μg / kg) was diluted with saline and injected intravenously on days 1 and 8. The changes in RTV of each group are shown in FIG. Antitumor activity was observed in the treated group with tumor regression.

CTG-2041
A tumor fragment of human angiosarcoma CTG-2041 was subcutaneously transplanted into the left abdomen of a female mouse. Tumor growth was monitored twice a week using digital calipers and the tumor volume was calculated using the formula below:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)

When the tumor volume ^{reached approximately 200 mm 3} , the animals were grouped into treatment or control groups based on the tumor volume and dosing was started on day 1. Each group consisted of 5 mice. Compound (1) was dissolved in DMSO and the solution was cryopreserved until before use. Compound (1) (100 μg / kg) was diluted with physiological saline and injected intravenously on the 1st and 8th days. The changes in RTV of each group are shown in FIG. Antitumor activity was observed in the treated group with tumor regression.

Pharmacological test example 23. Antitumor effect in a mouse model of endometrial cancer transplantation as monotherapy (Fig. 18)
HEC-108
15% FBS, cell suspension to adjust the human endometrial carcinoma cell line HEC-108 cultured in E-MEM, a concentration of 7.14 × 10 ⁷ cells / mL in a medium containing antibiotics Was prepared. The cell suspension was transplanted into the right ventral subcutaneous part of a thymus-deficient mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, 6 weeks old, Charles River Japan) in a volume of 150 μL. Thirteen days after cell transplantation (day 1), the length and width of the tumor in each mouse were measured using an electronic digital caliper (Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following formula:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)

Mice were randomly grouped based on TV (day 1). Each group consisted of 6 mice. Compound (1) was dissolved in DMSO and the solution was cryopreserved until before use. Compound (1) (180 μg / kg) was diluted with saline and injected intravenously on days 1 and 8. The changes in RTV of each group are shown in FIG. Antitumor activity was observed in the treated group with delayed tumor growth.

AN3CA
10% FBS, penicillin - human endometrial cancer cell line AN3CA cultured in E-MEM containing streptomycin, was adjusted to a concentration of 1.4 × 10 ⁸ cells / mL in Hank's balanced salt solution suspension cells the Nigoeki preparing the suspension Geltrex (TM) (thermo Fisher Scientific, # A1413202) and 1: 1 of cell suspension at a concentration of admixture 7 × 10 ⁷ cells / mL in a ratio Prepared. The cell suspension was transplanted into the right ventral subcutaneous part of a 6-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Twelve days after cell transplantation (day 1), the minor axis and major axis of each mouse tumor were measured using an electronic digital caliper (Digimatic (trademark) caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated using the following formula. did:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)

Based on the tumor volume obtained on the first day, the mice were grouped so that the average value of the tumor volume was equal between the groups. The experiment was performed with 5 mice per group. The test compound was dissolved in DMSO and the solution was stored frozen until before use. Immediately before administration, the storage solution was diluted with saline. The test compound in saline was intravenously administered once weekly at 180 μg / kg for 2 weeks (1st and 8th day). Antitumor activity was observed in the treated group with tumor regression.

Pharmacological test example 24. Growth Inhibition Assay in NCI-H23, HCC1954 and MES-SA Cell Lines NCI-H23 Growth Inhibition Assay In this assay, Compounds D-6 (Example 26), E-2, G-4, in human lung cancer cell line NCI-H23, The growth inhibitory activity of H-2, I-2, J-1, K-2, L-6, M-3 and N-1 was measured. NCI-H23 cells containing _{10% bovine serum albumin (FBS; Sigma, 172012) in a 5% CO 2} incubator (37 ° C.), and penicillin and streptomycin (Wako Pure Chemical Industries, Ltd., 168-23191). It was maintained in RPM-1640 (Wako Pure Chemical Industries, Ltd., 187-02021) medium. To each well of a 96-well plate (Becton, Dickinson and Company, 353219) was added 75 μL of NCI-H23 cell suspension adjusted to a concentration ^{of 4 × 10 4 cells / mL in culture medium to 5% of the cells.} Incubated overnight in a CO ₂ incubator (37 ° C.). The next day, 25 μL of each compound in the 3-fold dilution series suspended in culture medium was added to each well and the result was _{incubated in a 5% CO 2} incubator (37 ° C.) for 3 days. Cell viability was then determined with the EnVision 2103 Multilabel Reader (Perkin-Elmer, Wellesley, MA) by the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). The value of the cell-containing well without the test substrate was defined as 100%, and the value of the cell-free well was defined as 0%. The concentration of the test substrate required to inhibit cell growth by 50% (i.e., IC ₅₀ value) is calculated are summarized in Table 14.

HCC1954 Growth Inhibition Assay In this assay, compounds D-6 (Example 26), E-2, G-4, H-2, I-2, J-1, K-2, L-6 in the human breast cancer cell line HCC1954. , M-3 and N-1 growth inhibitory activity was measured. HCC 1954 cells containing 10% bovine serum albumin (FBS; Sigma, 172012) and penicillin and streptomycin (Wako Pure Chemical Industries, Ltd., 168-23191) in a 5% CO _{2 incubator (37 ° C.), 2 mM.} It was maintained in RPMM-1640 medium modified to contain L-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 4500 mg / L glucose, and 1500 mg / L sodium bicarbonate (ATCC 30-2001). To each well of a 96-well plate (Becton, Dickinson and Company, 353219), 75 ^{μL of HCC1954 cell suspension adjusted to a concentration of 4 × 10 4} cells / mL in culture medium was added and the cells were subjected to 5% CO ₂ Incubated overnight in an incubator (37 ° C.). The next day, 25 μL of each compound in the 3-fold dilution series suspended in culture medium was added to each well and the result was _{incubated in a 5% CO 2} incubator (37 ° C.) for 3 days. Cell viability was then determined with the EnVision 2103 Multilabel Reader (Perkin-Elmer, Wellesley, MA) by the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). The value of the cell-containing well without the test substrate was defined as 100%, and the value of the cell-free well was defined as 0%. The concentration of the test substrate required to inhibit cell growth by 50% (i.e., IC ₅₀ value) is calculated are summarized in Table 14.

MES-SA Growth Inhibition Assay In this assay, compounds D-6 (Example 26), E-2, G-4, H-2, I-2, J-1, K-2 in the human lung cancer cell line MES-SA. , L-6, M-3 and N-1 growth inhibitory activity was measured. MES-SA cells containing 10% bovine serum albumin (FBS; Sigma, 172012) and penicillin and streptomycin (Wako Pure Chemical Industries, Ltd., 168-23191) in _{a 5% CO 2 incubator (37 ° C.).} It was maintained in RPM-1640 (Wako Pure Chemical Industries, Ltd., 187-02021) medium. To each well of a 96-well plate (Becton, Dickinson and Company, 353219) was added 75 μL of MES-SA cell suspension adjusted to a concentration ^{of 4 × 10 4 cells / mL in culture medium to 5% of the cells.} Incubated overnight in a CO ₂ incubator (37 ° C.). The next day, 25 μL of each compound in the 3-fold dilution series suspended in culture medium was added to each well and the result was _{incubated in a 5% CO 2} incubator (37 ° C.) for 3 days. Cell viability was then determined with the EnVision 2103 Multilabel Reader (Perkin-Elmer, Wellesley, MA) by the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). The value of the cell-containing well without the test substrate was defined as 100%, and the value of the cell-free well was defined as 0%. The concentration of the test substrate required to inhibit cell growth by 50% (i.e., IC ₅₀ value) is calculated are summarized in Table 14.

Pharmacological test example 25. Molecular Mechanism of α-SMA Positive CAF Reduction Using In Vitro Culture System Expression of α-SMA is induced in BJ normal human fibroblasts upon co-culture with FaDu cells, and its expression is TGF-β-receptor It was attenuated by treatment with A83-01, a potent selective inhibitor of the body (Fig. 19A). These results suggested that TGF-β plays an important role as a mediator of α-SMA induction in this system. In addition, immunofluorescence analysis revealed that treatment with compound (1) interfered with TGF-β-induced α-SMA induction in BJ cells without growth inhibitory activity (FIGS. 19A, 20A).

Compound (1) did not significantly alter TGF-β-induced phosphorylation and Smad2 / 3 nuclear localization (Fig. 20D-20E), but it is essential for TGF-β-induced α-SMA expression. Reduced activation of the PI3K / AKT / mTOR pathway, which plays a role (FIGS. 19C and 19F, FIGS. 20B-20C). Moreover, TGF-β treatment enhanced β-tubulin expression and microtubule network formation abolished by co-treatment with compound (1) in BJ cells (FIG. 19D). Under the same experimental conditions, enhanced formation of focal adhesions, detected as punctate structures with antibodies against phosphorylated FAK in tyrosine-397, was found in compound (1) in BJ cells after stimulation with TGF-β. Decreased by treatment with (Fig. 19E). Many signaling complexes are assembled at focal adhesion sites, and these complexes deliver several downstream signals, including those involved in the PI3K / AKT / mTOR pathway. For example, see Sulzmaier et. Al. "FAK in cancer: mechanistic findings and clinical applications", Nature Reviews Cancer 2014, 14, 598-610. In fact, treatment with the FAK inhibitor de factinib clearly reduced the levels of TGF-β-induced α-SMA expression and S6 ribosomal protein phosphorylation in BJ cells (FIGS. 19G-19H). All the above phenomena were also observed in other normal human fibroblasts (TIG3 cells) (FIGS. 21A-21H).

Pharmacological test example 26. Bladder Cancer Cell Line Growth Inhibition Assay In this assay, the growth inhibitory activity of compound (1) in human bladder cell lines RT4, RT112 / 84, and UM-UC-3 was measured. RT4 and RT112 / 84 cells in 5% CO ₂ incubator (37 ° C.), 10% bovine serum albumin (FBS; SIGMA Life Science, 172012-500ML), and penicillin and streptomycin (FUJIFILM Wako Pure Chemical Corporation, 168-23191) ) Contained in RPMP-1640 (Wako Pure Chemical Industries, Ltd., 189-02025) medium. E-MEM containing UM-UC-3 cells in 5% CO ₂ incubator (37 ° C.), 10% FBS, 1 mM sodium pyruvate (FUJIFILM Wako Pure Chemical Corporation, 190-14881), and penicillin and streptomycin ( FUJIFILM Wako Pure Chemical Corporation, 051-07615) Maintained in medium. In each well of a 96-well plate (Corning, 3904), 5.55 × 10 ³ cells / mL (RT4 or UM-UC-3) or 3.33 × 10 ⁴ cells / mL (RT112 / 84) in culture medium. 90 μL of each cell suspension adjusted to concentration was added and the cells were _{incubated overnight in a 5% CO 2} incubator (37 ° C.). The next day, 10 μL of 3-fold dilution series of compound (1) suspended in culture medium was added to each well and the result was _{incubated in a 5% CO 2} incubator (37 ° C.) for 3 days. Cell viability was then determined with an ARVO-X4 Multimode Plate Reader (Perkin-Elmer, Wellesley, MA) by CellTiter-Glo® 2.0 Assay (Promega Corporation, G9243). The value of the cell-containing well without the test compound was defined as 100%, and the value of the cell-free well was defined as 0%. The concentration of test compound required to inhibit cell growth by 50% (i.e., IC ₅₀ value) was calculated shown in Table 15.

Pharmacological test example 27. Antitumor effect in HS-SY-II xenograft model in mice as monotherapy (Fig. 22)
Human synovial sarcoma cell line HS-SY-II cultured in DMEM containing 10% FBS and penicillin-streptomycin in Hanks balanced salt solution containing 50% Geltrex (Thermo Fisher Scientific), 1 × 10 Cell suspensions were prepared by adjusting to a concentration of ^{8 cells / mL.} The cell suspension was transplanted into the right ventral subcutaneous part of a 5-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Thirteen days after cell transplantation (day 1), the minor and major diameters of the tumor in each mouse were measured using an electronic digital caliper (Digimatic ™ caliper, Mitutoyo Co., Ltd.), and the tumor volume was measured according to the following formula. Was calculated:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Relative weight (RBW) = weight (day X) / weight (day 1)

Based on the tumor volume obtained on day 1, the mice were grouped so that the average tumor volume was substantially equal between the groups. The experiment was performed in each group consisting of 6 mice. Compound (1) was dissolved in DMSO and the solution was frozen and stored until before use. Immediately prior to administration, the storage solution was diluted with saline. The test compound in saline was intravenously administered once a week at 90 μg / kg or 180 μg / kg (Days 1 and 8) every two weeks. Tumor growth retardation was observed in the 90 μg / kg treatment group and tumor regression was observed in the 180 μg / kg treatment group.

Pharmacological test example 28. Antitumor effect in Hutu 80 xenograft model in mice as monotherapy (Fig. 23)
10% FBS, and Penicillin - human duodenal cell line HuTu 80 cultured in EMEM containing streptomycin at PBS, and adjusted a concentration of 3 × 10 ⁷ cells / mL, to prepare a cell suspension. The cell suspension was transplanted into the right ventral subcutaneous part of a 7-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, female, Nippon Charles River Co., Ltd.) in a volume of 100 μL. Seven days after cell transplantation (day 1), the minor and major diameters of the tumor in each mouse were measured using an electronic digital caliper (Digimatic ™ caliper, Mitutoyo Co., Ltd.), and the tumor volume was determined according to the following formula. Calculated:
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) / 2
Relative tumor volume (RTV) = tumor volume (day X) / tumor volume (day 1)
Relative weight (RBW) = weight (day X) / weight (day 1)

Based on the tumor volume obtained on day 1, the mice were grouped so that the average tumor volume was substantially equal between the groups. The experiment was performed in each group consisting of 6 mice. Compound (1) was dissolved in DMSO and the solution was frozen and stored until before use. Immediately prior to administration, the storage solution was diluted with saline. Saline test compounds were administered intravenously once weekly at 45, 90, or 180 μg / kg (Days 1 and 8) every two weeks. Tumor growth retardation was observed in the 45 and 90 μg / kg treatment groups and tumor regression was observed in the 180 μg / kg treatment group. Tumor regression (%) for compound (1) is shown in Table 16.

Equals and Ranges In the claims, articles such as "a", "an", "the" are one or one unless otherwise indicated or otherwise apparent from the context. Can mean more than. Claims or specifications that include "or" between one or more elements of the group are more than one, one, unless otherwise indicated or otherwise apparent from the context. Or if all groups of elements are present in a product or process and are used or otherwise related, they are considered to be satisfied. The present invention includes embodiments in which exactly one element of the group is present, used, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all group elements are present, used, or otherwise associated with a given product or process.

Further, the present invention is in all variations, combinations, permutations in which one or more restrictions, elements, clauses, descriptive terms from one or more of the listed claims are introduced into another claim. Including. For example, any claim subordinate to another claim may be modified to include one or more restrictions found in any other claim subordinate to the same basic claim. When an element is presented as a list in, for example, a Markush group format, each subgroup of that element is also disclosed and any element can be removed from the group. In general, where it is mentioned that the invention or aspects of the invention include specific elements and / or features, certain embodiments of the invention or aspects of the invention are such elements and / or features. It should be understood that it consists of or is essentially. For simplicity, such embodiments are not specifically indicated herein in this exact language. It is also noted that the terms "contains" and "contains" are intended to be open and allow the inclusion of additional elements or steps. If a range is given, the end point is included. Further, unless otherwise indicated, or otherwise apparent from the context and the understanding of those skilled in the art, the value expressed as a range is a unit of the lower limit of the range, unless otherwise explicitly required by the context. Up to one tenth, any specific value or subrange within the stated range in different embodiments of the invention can be assumed.

One of ordinary skill in the art will recognize many of the equivalents of the specific embodiments described herein, which can be confirmed at best using routine experiments. The scope of this embodiment as described herein is not intended to be limited to the above description, but rather as set forth in the appended claims. Those skilled in the art will appreciate that various modifications and modifications described herein may be made without departing from the spirit or scope of the invention as defined in the claims below.

Claims (87)

Equation (I):

During the ceremony:
^RN1 and ^RN2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or nitrogen protecting group, optionally here ^RN1 and R. ^N2 is linked together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, optionally here R ^Xa and R. ^Ya is linked together with the intervening atom to form a heterocyclyl that may be optionally substituted; and n is 1 or 2.
A compound represented by or a pharmaceutically acceptable salt thereof. The compound has the following formula:

The compound according to claim 1, which is one of the above or a pharmaceutically acceptable salt thereof. The compounds are:

The compound according to claim 1 or 2, provided that it is not a pharmaceutically acceptable salt thereof. Equation (II):

During the ceremony:
^RN1 and ^RN2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or nitrogen protecting group, optionally here ^RN1 and ^RN2. Linkes together with intervening atoms to form optionally substituted heterocyclyls or optionally substituted heteroaryls;
^RP1 and ^RP2 are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, optionally here R ^Xa and R. ^Ya is linked together with the intervening atom to form a heterocyclyl that may be optionally substituted; and m is 0 or 1.
A compound represented by or a pharmaceutically acceptable salt thereof. The compound has the following formula:

;
The compound according to claim 4, which is one of the above or a pharmaceutically acceptable salt thereof. Equation (III):

During the ceremony:
^RO is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;
RY} is hydrogen or -OR ^Ya ;
R ^Xa and R ^Ya are independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or oxygen protecting group, optionally here R ^Xa and R ^Ya. Are linked together with intervening atoms to form heterocyclyls that may be optionally substituted; and n is 1 or 2.
A compound represented by or a pharmaceutically acceptable salt thereof. The compound has the following formula:

;
The compound according to claim 6, which is one of the above or a pharmaceutically acceptable salt thereof. The compounds are:

The compound according to claim 6 or 7, provided that it is not a pharmaceutically acceptable salt thereof. Equation (IV):

During the ceremony:
^RO is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
^RP1 is hydrogen, an optionally substituted alkyl, an optionally substituted acyl, or an oxygen protecting group;
R ^X is hydrogen or ^{-OR Xa;}
R ^Y is hydrogen or -OR ^Ya; and R ^Xa and R ^Ya is independently hydrogen, optionally substituted alkyl, acyl substituted in any or oxygen protecting group, Or, optionally, R ^Xa and R ^Ya are linked together with the intervening atoms to form a heterocyclyl that may be optionally substituted.
A compound represented by or a pharmaceutically acceptable salt thereof. The compound has the formula:

The compound according to claim 9, which is a pharmaceutically acceptable salt thereof. The compound according to claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein n is 1. The compound according to claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein n is 2. The compound according to claim 4, wherein m is 1, or a pharmaceutically acceptable salt thereof. The compound according to claim 4, wherein m is 0, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1, 2, 4 or 5, or a pharmaceutically acceptable salt thereof, wherein at least one of ^RN1 and ^{RN2 is hydrogen.} The compound according to any one of claims 1, 2, 4 or 5, wherein both ^RN1 and ^{RN2 are hydrogen, or a pharmaceutically acceptable salt thereof.} R ^O is hydrogen, the compound or a pharmaceutically acceptable salt thereof according to any one of claims 6, 7, 9 or 10. And R ^O is optionally be an optionally substituted C _{1 to 6} alkyl, a compound or a pharmaceutically acceptable salt thereof according to any one of claims 6, 7, 9 or 10. R ^O is a good C _{1 to 3} alkyl substituted optionally, a compound or a pharmaceutically acceptable salts of claim 18. R ^O is a C _{1 to 3} alkyl unsubstituted compound or a pharmaceutically acceptable salt thereof according to claim 19. R ^O is methyl, the compound or its pharmaceutically acceptable salts according to claim 20. The compound according to claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein ^{RP2 is hydrogen.} Salts R ^P1 is, that is hydrogen, claim 1,2,4～7,9 or compound according to any one of 10, or their pharmaceutically acceptable. R ^X is hydrogen, according to claim 1, 4, 6 or 9 compound or its pharmaceutically acceptable salts, according to any one of. R ^X is an ^{-OR Xa,} compound according to any one of claims 1, 4, 6 or 9, or a pharmaceutically acceptable salts. R ^X is a -OH, A compound according to any one of claims 1, 4, 6 or 9, or a pharmaceutically acceptable salts. The compound according to any one of claims 1, 4, 6, or 9, or a pharmaceutically acceptable salt thereof, wherein ^{RY is hydrogen.} The compound according to any one of claims 1, 4, 6 or 9, or a pharmaceutically acceptable salt thereof, wherein ^{RY is −OR Xa.} The compound according to any one of claims 1, 4, 6, and 9, or a pharmaceutically acceptable salt thereof, wherein ^{RY is −OH.} Salts R ^X and R ^Y is hydrogen, A compound according to any one of claims 1, 4, 6 or 9, or their pharmaceutically acceptable. Salts R ^X and ^{R Y} is a -OH, A compound according to any one of claims 1, 4, 6 or 9, or their pharmaceutically acceptable. Salts and ^{R Y} is a -OH, claims 1, 4, 6, or a compound according to any one of 9, or their pharmaceutically acceptable; R ^X is hydrogen. The compound is

The compound according to claim 1 and a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. The compound is

The compound according to claim 1 and a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. The compound is

The compound according to claim 4 and a pharmaceutically acceptable salt thereof, which are selected from the group consisting of.
The compound is

The compound according to claim 4 and a pharmaceutically acceptable salt thereof, which are selected from the group consisting of. The compound is

The compound according to claim 6 and a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. The compound is

The compound according to claim 6 and a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. The compound is

The compound according to claim 9 and a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. A pharmaceutical composition comprising the compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof for use in the treatment of proliferative diseases. The compound according to claim 41 or a pharmaceutically acceptable salt thereof for use in the treatment of tumors or cancers. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein the tumor or cancer is characterized by angiogenesis, infiltration, or metastasis. The compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof for use in inhibiting the growth of a tumor or cancer. Treatment of a proliferative disorder in a subject, comprising administering to the subject the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40. How to do it. 45. The method of claim 45, wherein the proliferative disease is cancer or tumor. 46. The method of claim 46, wherein the cancer or tumor is characterized by angiogenesis, invasion, or metastasis. A tumor or cancer in a subject comprising administering to the subject the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40. A method for inhibiting growth. Use of the compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a proliferative disease. The use according to claim 49, wherein the proliferative disease is cancer or tumor. The use according to claim 50, wherein the cancer or tumor is characterized by angiogenesis, invasion, or metastasis. Use of the compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the growth of a tumor or cancer. Cancers or tumors are head and neck cancer, breast cancer, colonic rectal cancer, esophageal cancer, uterine cancer, ovarian cancer, endometrial cancer, sarcoma, gastric cancer, lung cancer, bladder cancer, small intestine The method of any one of claims 46-48, which is cancer or sweat gland cancer. 53. The method of claim 53, wherein the cancer or tumor is head and neck cancer. 54. The method of claim 54, wherein the head and neck cancer is a squamous cell carcinoma of the head and neck (SCCHN). 54. The method of claim 54, wherein the head and neck cancer is adenoid cystic carcinoma. 53. The method of claim 53, wherein the cancer or tumor is breast cancer. 58. The method of claim 57, wherein the breast cancer is HER2-positive breast cancer. 58. The method of claim 57, wherein the breast cancer is HER2-negative breast cancer. 58. The method of claim 57, wherein the breast cancer is triple negative breast cancer. 53. The method of claim 53, wherein the cancer or tumor is colorectal cancer. 53. The method of claim 53, wherein the cancer or tumor is esophageal cancer. 62. The method of claim 62, wherein the esophageal cancer is esophageal adenocarcinoma. 53. The method of claim 53, wherein the cancer or tumor is uterine cancer. 53. The method of claim 53, wherein the cancer or tumor is ovarian cancer. 53. The method of claim 53, wherein the cancer or tumor is a sarcoma. The method of claim 66, wherein the cancer is uterine sarcoma, fibrosarcoma, angiosarcoma, synovial sarcoma, soft tissue sarcoma, or intimal sarcoma. The method of claim 53, wherein the cancer is gastric cancer. The method of claim 53, wherein the cancer is small intestinal cancer. The method of claim 69, wherein the small intestine cancer is a small intestine adenocarcinoma. The method of claim 53, wherein the cancer is bladder cancer. The method of claim 71, wherein the bladder cancer is a urothelial cancer. The method of claim 53, wherein the cancer is lung cancer. The method of claim 73, wherein the cancer is non-small cell lung cancer. The method of claim 53, wherein the cancer is sweat gland cancer. The method of claim 75, wherein the cancer is sweat gland cancer. The method of claim 53, wherein the cancer is endometrial cancer. The method according to any one of claims 46 to 48, wherein the cancer is a rare cancer. The method of any one of claims 46-48, further comprising treating the subject with anti-EGFR (epidermal growth factor receptor) mAb therapy. The method of claim 79, wherein the cancer is head and neck squamous cell carcinoma (SCCHN). The method of claim 79 or 80, wherein the anti-EGFR (epidermal growth factor receptor) mAb is cetuximab. The method of any one of claims 46-48, further comprising treating the subject with HER2 (human epidermal growth factor receptor) mAb therapy. The method of claim 82, wherein the cancer is breast cancer. The method of claim 82 or 83, wherein the HER2 (human epidermal growth factor receptor) mAb is trastuzumab. The method of any one of claims 46-48, further comprising treating the subject with a programmed death 1 protein (PD-1) antibody. The method of any one of the preceding claims, further comprising treating the subject with radiation therapy. A kit comprising the compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 40.

Images